68 results on '"Hudry E"'
Search Results
2. Exosome-associated AAV vector as a robust and convenient neuroscience tool
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Hudry, E, Martin, C, Gandhi, S, György, B, Scheffer, D I, Mu, D, Merkel, S F, Mingozzi, F, Fitzpatrick, Z, Dimant, H, Masek, M, Ragan, T, Tan, S, Brisson, A R, Ramirez, S H, Hyman, B T, and Maguire, C A
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- 2016
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3. Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease
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DaRocha-Souto, B., Coma, M., Pérez-Nievas, B.G., Scotton, T.C., Siao, M., Sánchez-Ferrer, P., Hashimoto, T., Fan, Z., Hudry, E., Barroeta, I., Serenó, L., Rodríguez, M., Sánchez, M.B., Hyman, B.T., and Gómez-Isla, T.
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- 2012
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4. Erratum: Exosome-associated AAV vector as a robust and convenient neuroscience tool
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Hudry, E, Martin, C, Gandhi, S, György, B, Scheffer, D I, Mu, D, Merkel, S F, Mingozzi, F, Fitzpatrick, Z, Dimant, H, Masek, M, Ragan, T, Tan, S, Brisson, A R, Ramirez, S H, Hyman, B T, and Maguire, C A
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- 2016
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5. Abnormal synaptic Ca2+ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice
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Eikermann-Haerter, K., Arbel-Ornath, M., Yalcin, N., Yu, E.S., Kuchibhotla, K.V., Yuzawa, I., Hudry, E., Willard, C.R., Climov, M., Keles, F., Belcher, A.M., Sengul, B., Negro, A., Rosen, I.A., Arreguin, A., Ferrari, M.D., Maagdenberg, A.M.J.M. van den, Bacskai, B.J., and Ayata, C.
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- 2015
6. Mechanical behaviour of aluminium foams for various deformation paths. Experiment and modelling
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Chastel, Yvan, Hudry, E., Forest, Samuel, Peytour, C., Centre de Mise en Forme des Matériaux (CEMEF), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre des Matériaux (MAT), ed. J. Banhart, M.F.Ashby, and N.A. Fleck
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[PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 1999
7. Distinct Dendritic Spine and Nuclear Phases of Calcineurin Activation after Exposure to Amyloid- Revealed by a Novel Fluorescence Resonance Energy Transfer Assay
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Wu, H.-Y., primary, Hudry, E., additional, Hashimoto, T., additional, Uemura, K., additional, Fan, Z.-Y., additional, Berezovska, O., additional, Grosskreutz, C. L., additional, Bacskai, B. J., additional, and Hyman, B. T., additional
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- 2012
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8. Abnormal Synaptic Morphology and Neuronal Ca2+-Homeostasis in Migraine Mutant Mice
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Eikermann-Haerter, K., Arbel-Ornath, M., Kuchibhotla, K., Yu, E.S., Lattarullo, C., Thyssen, D., Yalcin, N., Rosen, I., Arreguin, A., Climov, M., Keles, F., Belcher, A., Sengul, B., Negro, A., Hudry, E., Ferrari, M.D., Maagdenberg, A.M. van den, Bacskai, B., and Ayata, C.
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cortical spreading depression ,migraine ,familial hemiplegic migraine
9. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease
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Elizabeth K. Kharitonova, Alyssa N. Russ, Eloise Hudry, Alona Muzikansky, Austin Snyder, Sudeshna Das, Maria Calvo-Rodriguez, Monica Garcia-Alloza, Brian J. Bacskai, Zhanyun Fan, Alberto Serrano-Pozo, Steven S. Hou, Biomedicina, Biotecnología y Salud Pública, [Calvo-Rodriguez,M, Hou,SS, Snyder,AC, Kharitonova,EK, Russ,AN, Das,S, Fan,Z, Serrano-Pozo,A, Hudry,E, Bacskai,BJ] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, MA, USA. [Muzikansky,A] Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. [Garcia-Alloza,M] Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain., This work was supported by NIHR01AG0442603, S10 RR025645 and R56AG060974 (BJB), and and by the Tosteson & Fund for Medical Discovery and the BrightFocus Foundation A2019488F (MCR). MSBB study was supported by the grants AG046170, AG054014, AG057440 and AG057907 from the NIH/National Institute on Aging (NIA). A.S.-P. was supported by the Alzheimer’s Association (AACF-17-524184) and the National Institute for Neurodegenerative Diseases and Stroke (NINDS R25NS065743).
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0301 basic medicine ,Male ,Plomo ,General Physics and Astronomy ,Mitochondrion ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immunologic Techniques::Immunohistochemistry [Medical Subject Headings] ,Mice ,0302 clinical medicine ,Cytosol ,Microscopía ,Enfermedad de Alzheimer ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,lcsh:Science ,Anatomy::Nervous System::Neurons [Medical Subject Headings] ,Cells, Cultured ,Mitocondrias ,Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria [Medical Subject Headings] ,Membrane Potential, Mitochondrial ,Neurons ,Microscopy ,Multidisciplinary ,biology ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Molecular Probe Techniques::Blotting, Western [Medical Subject Headings] ,Brain ,Neurodegenerative Diseases ,Immunohistochemistry ,Cell biology ,Mitochondria ,Chemicals and Drugs::Inorganic Chemicals::Elements::Metals, Alkaline Earth::Calcium [Medical Subject Headings] ,Encéfalo ,Alzheimer disease ,Neuron death ,Genetically modified mouse ,Cell death ,Programmed cell death ,Amyloid ,Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings] ,Amyloid beta ,Science ,Blotting, Western ,chemistry.chemical_element ,Check Tags::Male [Medical Subject Headings] ,Calcium ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Calcio ,Diseases::Nervous System Diseases::Neurodegenerative Diseases [Medical Subject Headings] ,Animals ,Uniporter ,Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytosol [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] ,Amiloide ,Phenomena and Processes::Cell Physiological Phenomena::Membrane Potentials::Membrane Potential, Mitochondrial [Medical Subject Headings] ,General Chemistry ,Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings] ,Muerte celular ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Genes ,Lead ,Anatomy::Cells::Cells, Cultured [Medical Subject Headings] ,biology.protein ,lcsh:Q ,Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings] ,030217 neurology & neurosurgery - Abstract
Mitochondria contribute to shape intraneuronal Ca2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (A beta) causes cytosolic Ca2+ overload, but the effects of A beta on mitochondrial Ca2+ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral beta -amyloidosis. Naturally secreted soluble A beta applied onto the healthy brain increases Ca2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca2+ transporter genes, but upregulation in the genes related to mitochondrial Ca2+ efflux pathways, suggesting a counteracting effect to avoid Ca2+ overload. We propose lowering neuronal mitochondrial Ca2+ by inhibiting the mitochondrial Ca2+ uniporter as a novel potential therapeutic target against AD. Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral beta -amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular A beta oligomers and the mitochondrial calcium uniporter.
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- 2020
10. Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice
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Raquel Larramona-Arcas, Marta Martinez-Vicente, Eleanna Kara, Miquel Vila, Maria D. Ganfornina, Candela González-Arias, Tamara García-Barrera, Gertrudis Perea, Elena Galea, Antonia Gutierrez, Raquel Pascua-Maestro, Javier Vitorica, Eloise Hudry, Roser Masgrau, José Luis Gómez-Ariza, Fundació La Marató de TV3, Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, [Larramona-Arcas,R, Vila,M, Galea,E, Masgrau,R] Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, and, Institut de Neurociències (INc), Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Catalonia, Spain. [González-Arias,C, Perea,G] Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. [Gutiérrez,A] Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomedica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Gutiérrez,A, Vitorica,J, Martinez-Vicente,M, Vila,M] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Vitorica,J] Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain. [García-Barrera,T, Gómez-Ariza,JL] Departamento de Química, Facultad de Ciencias Experimentales, Campus de El Carmen, Centro de Investigación en Recursos Naturales, Salud y Medio Ambiente (RENSMA), Universidad de Huelva, Huelva, Spain. [Pascua-Maestro,R, Ganfornina,MD] Departamento de Bioquímica y Biología Molecular y Fisiología, Instituto de Biología y Genética Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain. [Kara,E, Hudry,E] Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. [Kara,E] Present Address: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland. [Martinez-Vicente,M, Vila,M] Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain. [Vila,M, Galea,E] CREA, Passeig Lluís Companys 23, Barcelona, Catalonia, Spain., This research was mainly funded by grants TV3–20141430, TV3–20141432 and TV3–20141431 from La Marató de Televisió de Catalunya (TV3) to EG, AG and JV respectively, and grants 2107 SGR1780 from AGAUR (Generalitat de Catalunya) to RM, 2017 SGR547 from AGAUR (Generalitat de Catalunya) to EG, BFU2016–75107-P from Ministerio de Economia, Industria y Competividad (Spanish Government) to GP, BFU2015–68149-R from Ministerio de Ciencia e Innovación (Spanish Government) and co financed by European Regional Development Fund to MDG and PI18/01557 from Instituto de Salud Carlos III (ISCiii, Spanish Government) co-financed by FEDER funds from European Union to AG. CG-A was awarded a PhD fellowship BES-2017-080303 from Ministerio de Economía, Industria y Competividad (Spanish Government)., and Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular
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0301 basic medicine ,Apolipoprotein E ,Astrocitos ,Male ,Chemicals and Drugs::Lipids::Membrane Lipids::Sterols::Cholesterol [Medical Subject Headings] ,Chemicals and Drugs::Lipids::Lipoproteins::Apolipoproteins::Apolipoproteins E::Apolipoprotein E3 [Medical Subject Headings] ,Apolipoprotein E4 ,Apolipoprotein E3 ,lcsh:Geriatrics ,Hippocampal formation ,Lipidome ,Hippocampus ,lcsh:RC346-429 ,0302 clinical medicine ,Chemicals and Drugs::Lipids::Lipoproteins::Apolipoproteins::Apolipoproteins E::Apolipoprotein E4 [Medical Subject Headings] ,Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Cytoplasmic Vesicles::Lysosomes [Medical Subject Headings] ,Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Sex [Medical Subject Headings] ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Dementia::Alzheimer Disease [Medical Subject Headings] ,Chemicals and Drugs::Biological Factors::Blood Coagulation Factors::Calcium [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic [Medical Subject Headings] ,Anatomy::Nervous System::Neurons [Medical Subject Headings] ,Calcium signaling ,Neurons ,Chemistry ,Purinergic receptor ,Long-term potentiation ,Señalización del calcio ,Lipidómica ,Lysosome ,Cell biology ,medicine.anatomical_structure ,Cholesterol ,Female ,lipids (amino acids, peptides, and proteins) ,Sex ,Purinergic receptors ,Astrocyte ,Research Article ,Receptores purinérgicos ,APOE4 ,Anatomy::Nervous System::Neuroglia::Astrocytes [Medical Subject Headings] ,Check Tags::Male [Medical Subject Headings] ,Mice, Transgenic ,Sexo ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Apolipoproteína E4 ,Alzheimer Disease ,mental disorders ,Extracellular ,medicine ,Animals ,Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hippocampus [Medical Subject Headings] ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,lcsh:RC952-954.6 ,030104 developmental biology ,Check Tags::Female [Medical Subject Headings] ,Astrocytes ,Calcium ,Neurology (clinical) ,Lysosomes ,human activities ,030217 neurology & neurosurgery ,Lisosomas - Abstract
© The Author(s)., [Background]: The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer’s disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+signaling in astrocytes., [Methods]: Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed., [Results]: We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes., [Conclusions]: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD., This research was mainly funded by grants TV3–20141430, TV3–20141432 and TV3–20141431 from La Marató de Televisió de Catalunya (TV3) to EG, AG and JV respectively, and grants 2107 SGR1780 from AGAUR (Generalitat de Catalunya) to RM, 2017 SGR547 from AGAUR (Generalitat de Catalunya) to EG, BFU2016–75107-P from Ministerio de Economia, Industria y Competividad (Spanish Government) to GP, BFU2015–68149-R from Ministerio de Ciencia e Innovación (Spanish Government) and co-financed by European Regional Development Fund to MDG and PI18/01557 from Instituto de Salud Carlos III (ISCiii, Spanish Government) co-financed by FEDER funds from European Union to AG. CG-A was awarded a PhD fellowship BES-2017-080303 from Ministerio de Economía, Industria y Competividad (Spanish Government).
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- 2020
11. Liver injury in cynomolgus monkeys following intravenous and intrathecal scAAV9 gene therapy delivery.
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Hudry E, Aihara F, Meseck E, Mansfield K, McElroy C, Chand D, Tukov FF, and Penraat K
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- Animals, Humans, Macaca fascicularis genetics, Administration, Intravenous, Dependovirus genetics, Dependovirus metabolism, Genetic Vectors genetics, Genetic Therapy, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury therapy
- Abstract
Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellular necrosis and deteriorating clinical condition. These transient acute liver injury marker elevations occur from 3-4 days post intravenous administration to ∼2 weeks post intrathecal administration. No transaminase elevation or microscopic changes were observed with intrathecal administration of empty capsids or a "promoterless genome" vector, suggesting that liver injury after cerebrospinal fluid dosing in nonhuman primates is driven by viral transduction and transgene expression. Co-administration of prednisolone after intravenous or intrathecal dosing did not prevent liver enzyme or microscopic changes despite a reduction of T lymphocyte infiltration in liver tissue. Similarly, co-administration of rituximab/everolimus with intrathecal dosing failed to block AAV-driven hepatotoxicity. Self-complementary AAV-induced acute liver injury appears to correlate with high hepatocellular vector load, macrophage activation, and type 1 interferon innate virus-sensing pathway responses. The current work characterizes key aspects pertaining to early AAV-driven hepatotoxicity in cynomolgus macaques, highlighting the usefulness of this nonclinical species in that context., Competing Interests: Declaration of interests E.H., F.A., K.M., and K.P. are employees of Novartis Institutes for BioMedical Research. E.M., C.M., D.C., and F.F.T. are employees of Novartis Pharmaceuticals Corporation. All authors own Novartis stock or other equities., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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12. An Engineered Adeno-Associated Virus Capsid Mediates Efficient Transduction of Pericytes and Smooth Muscle Cells of the Brain Vasculature.
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Ramirez SH, Hale JF, McCarthy S, Cardenas CL, Dona KNUG, Hanlon KS, Hudry E, Cruz D, Ng C, Das S, Nguyen DM, Nammour J, Bennett RE, Andrews AM, Musolino PL, and Maguire CA
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- Humans, Transduction, Genetic, Pericytes metabolism, Capsid Proteins metabolism, Brain metabolism, Myocytes, Smooth Muscle metabolism, Genetic Vectors genetics, Capsid metabolism, Dependovirus metabolism
- Abstract
Neurodegeneration and cerebrovascular disease share an underlying microvascular dysfunction that may be remedied by selective transgene delivery. To date, limited options exist in which cellular components of the brain vasculature can be effectively targeted by viral vector therapeutics. In this study, we characterize the first engineered adeno-associated virus (AAV) capsid mediating high transduction of cerebral vascular pericytes and smooth muscle cells (SMCs). We performed two rounds of in vivo selection with an AAV capsid scaffold displaying a heptamer peptide library to isolate capsids that traffic to the brain after intravenous delivery. One identified capsid, termed AAV-PR, demonstrated high transduction of the brain vasculature, in contrast to the parental capsid, AAV9, which transduces mainly neurons and astrocytes. Further analysis using tissue clearing, volumetric rendering, and colocalization revealed that AAV-PR enabled high transduction of cerebral pericytes located on small-caliber vessels and SMCs in the larger arterioles and penetrating pial arteries. Analysis of tissues in the periphery indicated that AAV-PR also transduced SMCs in large vessels associated with the systemic vasculature. AAV-PR was also able to transduce primary human brain pericytes with higher efficiency than AAV9. Compared with previously published AAV capsids tropisms, AAV-PR represents the first capsid to allow for effective transduction of brain pericytes and SMCs and offers the possibility of genetically modulating these cell types in the context of neurodegeneration and other neurological diseases.
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- 2023
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13. VWA3A -derived ependyma promoter drives increased therapeutic protein secretion into the CSF.
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Carrell EM, Chen YH, Ranum PT, Coffin SL, Singh LN, Tecedor L, Keiser MS, Hudry E, Hyman BT, and Davidson BL
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Recombinant adeno-associated viral vectors (rAAVs) are a promising strategy to treat neurodegenerative diseases because of their ability to infect non-dividing cells and confer long-term transgene expression. Despite an ever-growing library of capsid variants, widespread delivery of AAVs in the adult central nervous system remains a challenge. We have previously demonstrated successful distribution of secreted proteins by infection of the ependyma, a layer of post-mitotic epithelial cells lining the ventricles of the brain and central column of the spinal cord, and subsequent protein delivery via the cerebrospinal fluid (CSF). Here we define a functional ependyma promoter to enhance expression from this cell type. Using RNA sequencing on human autopsy samples, we identified disease- and age-independent ependyma gene signatures. Associated promoters were cloned and screened as libraries in mouse and rhesus macaque to reveal cross-species function of a human DNA-derived von Willebrand factor domain containing 3A ( VWA3A ) promoter. When tested in mice, our VWA3A promoter drove strong, ependyma-localized expression of eGFP and increased secreted ApoE protein levels in the CSF by 2-12× over the ubiquitous iCAG promoter., Competing Interests: B.L.D. serves an advisory role with equity in Latus Biosciences, Patch Bio, Voyager Therapeutics, Carbon Biosciences, Spirovant Biosciences, Resilience, Panorama Medicines, Saliogen, and Homology Medicines. She has sponsored research from Novartis, Roche, Latus, Homology Medicines, Saliogen, and Spirovant. B.T.H. is on the scientific advisory board of Latus Bio and has an equity interest. He has a family member who works at Novartis and owns stock in Novartis; he serves on the SAB of Dewpoint and owns stock. He serves on a scientific advisory board or is a consultant for AbbVie, Aprinoia Therapeutics, Arvinas, Avrobio, Axial, Biogen, BMS, Cure Alz Fund, Cell Signaling, Dewpoint, Eisai, Genentech, Ionis, Latus, Novartis, Sangamo, Sanofi, Seer, Takeda, the US Department of Justice, Vigil, and Voyager., (© 2023 The Authors.)
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- 2023
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14. Neuronally Derived Soluble Abeta Evokes Cell-Wide Astrocytic Calcium Dysregulation in Absence of Amyloid Plaques in Vivo .
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Kelly P, Sanchez-Mico MV, Hou SS, Whiteman S, Russ A, Hudry E, Arbel-Ornath M, Greenberg SM, and Bacskai BJ
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- Mice, Male, Female, Animals, Amyloid beta-Peptides, Calcium, Astrocytes physiology, Plaque, Amyloid pathology, Mice, Transgenic, Amyloid beta-Protein Precursor genetics, Disease Models, Animal, Alzheimer Disease pathology
- Abstract
The key pathologic entities driving the destruction of synaptic function and integrity during the evolution of Alzheimer's disease (AD) remain elusive. Astrocytes are structurally and functionally integrated within synaptic and vascular circuitry and use calcium-based physiology to modulate basal synaptic transmission, vascular dynamics, and neurovascular coupling, which are central to AD pathogenesis. We used high-resolution multiphoton imaging to quantify all endogenous calcium signaling arising spontaneously throughout astrocytic somata, primary processes, fine processes, and capillary endfeet in the brain of awake APP/PS1 transgenic mice (11 male and 6 female mice). Endogenous calcium signaling within capillary endfeet, while surprisingly as active as astrocytic fine processes, was reduced ∼50% in the brain of awake APP/PS1 mice. Cortical astrocytes, in the presence of amyloid plaques in awake APP/PS1 mice, had a cell-wide increase in intracellular calcium associated with an increased frequency, amplitude, and duration of spontaneous calcium signaling. The cell-wide astrocytic calcium dysregulation was not directly related to distance to amyloid plaques. We could re-create the cell-wide intracellular calcium dysregulation in the absence of amyloid plaques following acute exposure to neuronally derived soluble Abeta from Tg2576 transgenic mice, in the living brain of male C57/Bl6 mice. Our findings highlight a role for astrocytic calcium pathophysiology in soluble-Abeta mediated neurodegenerative processes in AD. Additionally, therapeutic strategies aiming to protect astrocytic calcium physiology from soluble Abeta-mediated toxicity may need to pharmacologically enhance calcium signaling within the hypoactive capillary endfeet while reducing the hyperactivity of spontaneous calcium signaling throughout the rest of the astrocyte. SIGNIFICANCE STATEMENT Astrocytic calcium signaling is functionally involved in central pathologic processes of Alzheimer's disease. We quantified endogenous calcium signaling arising spontaneously in the brain of awake APP/PS1 mice, as general anesthesia suppressed astrocytic calcium signaling. Cell-wide astrocytic calcium dysregulation was not related to distance to amyloid plaques but mediated in part by neuronally derived soluble Abeta, supporting a role for astrocytes in soluble-Abeta mediated neurodegeneration. Spontaneous calcium signaling is largely compartmentalized and capillary endfeet were as active as fine processes but hypoactive in the presence of amyloid plaques, while the rest of the astrocyte became hyperactive. The cell-wide calcium pathophysiology in astrocytes may require a combination therapeutic strategy for hypoactive endfeet and astrocytic hyperactivity., (Copyright © 2023 the authors.)
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- 2023
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15. Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates.
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Johnson EW, Sutherland JJ, Meseck E, McElroy C, Chand DH, Tukov FF, Hudry E, and Penraat K
- Abstract
In nonhuman primates (NHPs), adeno-associated virus serotype 9 (AAV9) vectorized gene therapy can cause asymptomatic microscopic injury to dorsal root ganglia (DRG) and trigeminal ganglia (TG) somatosensory neurons, causing neurofilament light chain (NfL) to diffuse into cerebrospinal fluid (CSF) and blood. Data from 260 cynomolgus macaques administered vehicle or AAV9 vectors (intrathecally or intravenously) were analyzed to investigate NfL as a soluble biomarker for monitoring DRG/TG microscopic findings. The incidence of key DRG/TG findings with AAV9 vectors was 78% (maximum histopathology severity, moderate) at 2-12 weeks after the dose. When examined up to 52 weeks after the dose, the incidence was 42% (maximum histopathology severity, minimal). Terminal NfL concentrations in plasma, serum, and CSF correlated with microscopic severity. After 52 weeks, NfL returned to pre-dose baseline concentrations, correlating with microscopic findings of lesser incidence and/or severity compared with interim time points. Blood and CSF NfL concentrations correlated with asymptomatic DRG/TG injury, suggesting that monitoring serum and plasma concentrations is as useful for assessment as more invasive CSF sampling. Longitudinal assessment of NfL concentrations related to microscopic findings associated with AAV9 administration in NHPs indicates NfL could be a useful biomarker in nonclinical toxicity testing. Caution should be applied for any translation to humans., Competing Interests: E.M., C.M., D.H.C., and F.F.T. are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ. E.W.J., J.J.S., E.H., and K.P. are employees of Novartis Institutes for BioMedical Research, Cambridge, MA. All authors own Novartis stock or other equities., (© 2022 The Authors.)
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- 2022
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16. APOE4 derived from astrocytes leads to blood-brain barrier impairment.
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Jackson RJ, Meltzer JC, Nguyen H, Commins C, Bennett RE, Hudry E, and Hyman BT
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- Humans, Animals, Mice, Apolipoprotein E3 genetics, Blood-Brain Barrier metabolism, Matrix Metalloproteinase 9, Protein Isoforms metabolism, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Astrocytes metabolism
- Abstract
Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood-brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood-brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood-brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood-brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood-brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood-brain barrier., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
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17. Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus Macaques.
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Meseck EK, Guibinga G, Wang S, McElroy C, Hudry E, and Mansfield K
- Subjects
- Animals, Green Fluorescent Proteins genetics, Macaca fascicularis genetics, Sensory Receptor Cells, Tissue Distribution, Dependovirus genetics, Dependovirus metabolism, Genetic Vectors
- Abstract
Biodistribution of self-complementary adeno-associated virus-9 (scAAV9)-chicken β-actin promoter-green fluorescent protein (GFP) was assessed in juvenile cynomolgus macaques infused intrathecally via lumbar puncture or the intracisterna magna (1.0×10
13 or 3.0×1013 vg/animal), with necropsy 28 days later. Our results characterized central nervous system biodistribution compared with systemic organs/tissues by droplet digital polymerase chain reaction for DNA and in situ hybridization. Green fluorescent protein expression was characterized by Meso Scale Discovery electrochemiluminescence immunosorbent assay and immunohistochemistry (IHC). Biodistribution was widespread but variable, with vector DNA and GFP expression greatest in the spinal cord, dorsal root ganglia (DRG), and certain systemic tissues (e.g., liver), with low concentrations in many brain regions despite direct cerebrospinal fluid administration. Transduction and expression were observed primarily in perivascular astrocytes in the brain, with a paucity in neurons. Greater GFP expression was observed in hepatocytes, striated myocytes, cardiomyocytes, spinal cord lower motor neurons, and DRG sensory neurons by IHC. These results should be considered when evaluating scAAV9-based intrathecal delivery with the current expression cassette as a modality for neurologic diseases that require widespread brain neuronal expression. This capsid/expression cassette combination may be better suited for diseases that express a secreted protein and/or do not require widespread brain neuronal transduction.- Published
- 2022
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18. Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer's disease.
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Serrano-Pozo A, Li Z, Noori A, Nguyen HN, Mezlini A, Li L, Hudry E, Jackson RJ, Hyman BT, and Das S
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- Humans, Mice, Animals, Aged, Alleles, Transcriptome genetics, Brain metabolism, Plaque, Amyloid genetics, Apolipoproteins E genetics, Alzheimer Disease genetics
- Abstract
The roles of APOE ε4 and APOE ε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that APOE alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in APOE ε4 and downregulated in APOE ε2 carriers relative to APOE ε3 homozygotes. This microglia- APOE cluster is enriched in phagocytosis-including TREM2 and TYROBP -and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in APOE knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human APOE -linked expression patterns. Thus, the APOE ε4 allele might prime microglia towards a phagocytic and proinflammatory state through an APOE-TREM2-TYROBP axis in normal aging as well as in Alzheimer's disease., Competing Interests: Competing interests The authors declare no competing interests.
- Published
- 2021
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19. Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation.
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Amaral AC, Perez-Nievas BG, Siao Tick Chong M, Gonzalez-Martinez A, Argente-Escrig H, Rubio-Guerra S, Commins C, Muftu S, Eftekharzadeh B, Hudry E, Fan Z, Ramanan P, Takeda S, Frosch MP, Wegmann S, and Gomez-Isla T
- Abstract
It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies., Competing Interests: Teresa Gómez-Isla participated as speaker in an Eli Lilly and Company-sponsored educational symposium and serves in an Eli Lilly Data Monitoring Committee. All other authors declare no competing interests., (© 2021 The Authors.)
- Published
- 2021
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20. Gene therapy for Alzheimer's disease targeting CD33 reduces amyloid beta accumulation and neuroinflammation.
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Griciuc A, Federico AN, Natasan J, Forte AM, McGinty D, Nguyen H, Volak A, LeRoy S, Gandhi S, Lerner EP, Hudry E, Tanzi RE, and Maguire CA
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Amyloid beta-Protein Precursor genetics, Animals, Brain metabolism, Brain pathology, Dependovirus genetics, Disease Models, Animal, Humans, Mice, Mice, Transgenic genetics, Microglia metabolism, Microglia pathology, Plaque, Amyloid genetics, Plaque, Amyloid pathology, Sialic Acid Binding Ig-like Lectin 3 antagonists & inhibitors, Alzheimer Disease therapy, Genetic Therapy, Presenilin-1 genetics, Sialic Acid Binding Ig-like Lectin 3 genetics
- Abstract
Neuroinflammation is a key contributor to the pathology of Alzheimer's disease (AD). CD33 (Siglec-3) is a transmembrane sialic acid-binding receptor on the surface of microglial cells. CD33 is upregulated on microglial cells from post-mortem AD patient brains, and high levels of CD33 inhibit uptake and clearance of amyloid beta (Aβ) in microglial cell cultures. Furthermore, knockout of CD33 reduces amyloid plaque burden in mouse models of AD. Here, we tested whether a gene therapy strategy to reduce CD33 on microglia in AD could decrease Aβ plaque load. Intracerebroventricular injection of an adeno-associated virus (AAV) vector-based system encoding an artificial microRNA targeting CD33 (miRCD33) into APP/PS1 mice reduced CD33 mRNA and TBS-soluble Aβ40 and Aβ42 levels in brain extracts. Treatment of APP/PS1 mice with miRCD33 vector at an early age (2 months) was more effective at reducing Aβ plaque burden than intervening at later times (8 months). Furthermore, early intervention downregulated several microglial receptor transcripts (e.g. CD11c, CD47 and CD36) and pro-inflammatory activation genes (e.g. Tlr4 and Il1b). Marked reductions in the chemokine Ccl2 and the pro-inflammatory cytokine Tnfα were observed at the protein level in the brain of APP/PS1 mice treated with miRCD33 vector. Overall, our data indicate that CD33 is a viable target for AAV-based knockdown strategies to reduce AD pathology. One Sentence Summary: A gene therapy approach for Alzheimer's disease using adeno-associated virus vector-based knockdown of CD33 reduced amyloid beta accumulation and neuroinflammation., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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21. Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice.
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Larramona-Arcas R, González-Arias C, Perea G, Gutiérrez A, Vitorica J, García-Barrera T, Gómez-Ariza JL, Pascua-Maestro R, Ganfornina MD, Kara E, Hudry E, Martinez-Vicente M, Vila M, Galea E, and Masgrau R
- Subjects
- Alzheimer Disease metabolism, Animals, Apolipoprotein E3 metabolism, Cholesterol metabolism, Female, Hippocampus metabolism, Male, Mice, Transgenic, Neurons metabolism, Apolipoprotein E3 genetics, Apolipoprotein E4 genetics, Astrocytes metabolism, Calcium metabolism, Lysosomes metabolism
- Abstract
Background: The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer's disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca
2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+ signaling in astrocytes., Methods: Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed., Results: We found potentiation of ATP-elicited Ca2+ responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes., Conclusions: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.- Published
- 2020
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22. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease.
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Calvo-Rodriguez M, Hou SS, Snyder AC, Kharitonova EK, Russ AN, Das S, Fan Z, Muzikansky A, Garcia-Alloza M, Serrano-Pozo A, Hudry E, and Bacskai BJ
- Subjects
- Animals, Blotting, Western, Cells, Cultured, Cytosol metabolism, Immunohistochemistry, Male, Membrane Potential, Mitochondrial physiology, Mice, Mice, Inbred C57BL, Alzheimer Disease metabolism, Brain metabolism, Calcium metabolism, Mitochondria metabolism, Neurodegenerative Diseases metabolism, Neurons cytology, Neurons metabolism
- Abstract
Mitochondria contribute to shape intraneuronal Ca
2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca2+ overload, but the effects of Aβ on mitochondrial Ca2+ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral β-amyloidosis. Naturally secreted soluble Aβ applied onto the healthy brain increases Ca2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca2+ transporter genes, but upregulation in the genes related to mitochondrial Ca2+ efflux pathways, suggesting a counteracting effect to avoid Ca2+ overload. We propose lowering neuronal mitochondrial Ca2+ by inhibiting the mitochondrial Ca2+ uniporter as a novel potential therapeutic target against AD.- Published
- 2020
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23. Selection of an Efficient AAV Vector for Robust CNS Transgene Expression.
- Author
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Hanlon KS, Meltzer JC, Buzhdygan T, Cheng MJ, Sena-Esteves M, Bennett RE, Sullivan TP, Razmpour R, Gong Y, Ng C, Nammour J, Maiz D, Dujardin S, Ramirez SH, Hudry E, and Maguire CA
- Abstract
Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent and sustained in two mouse strains (C57BL/6 and BALB/c), making it a highly useful capsid for CNS transduction of mice. Future work in large animal models will test the translation potential of AAV-F., (© 2019 The Author(s).)
- Published
- 2019
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24. Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1.
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Prabhakar S, Cheah PS, Zhang X, Zinter M, Gianatasio M, Hudry E, Bronson RT, Kwiatkowski DJ, Stemmer-Rachamimov A, Maguire CA, Sena-Esteves M, Tannous BA, and Breakefield XO
- Abstract
Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal nodules, subependymal giant cell astrocytomas, and cortical tubers in the human brain. Neurological manifestations in TSC include intellectual disability, autism, hydrocephalus, and epilepsy. In a stochastic mouse model of TSC1 brain lesions, complete loss of Tsc1 is achieved in homozygous Tsc1- floxed mice in a subpopulation of neural cells in the brain by intracerebroventricular (i.c.v.) injection at birth of an adeno-associated virus (AAV) vector encoding Cre recombinase. This results in median survival of 38 days and brain pathology, including subependymal lesions and enlargement of neuronal cells. Remarkably, when these mice were injected intravenously on day 21 with an AAV9 vector encoding hamartin, most survived at least up to 429 days in apparently healthy condition with marked reduction in brain pathology. Thus, a single intravenous administration of an AAV vector encoding hamartin restored protein function in enough cells in the brain to extend lifespan in this TSC1 mouse model.
- Published
- 2019
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25. Experimental evidence for the age dependence of tau protein spread in the brain.
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Wegmann S, Bennett RE, Delorme L, Robbins AB, Hu M, McKenzie D, Kirk MJ, Schiantarelli J, Tunio N, Amaral AC, Fan Z, Nicholls S, Hudry E, and Hyman BT
- Subjects
- Alzheimer Disease metabolism, Animals, Cell Line, Disease Models, Animal, Disease Progression, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons metabolism, Brain metabolism, tau Proteins metabolism
- Abstract
The incidence of Alzheimer's disease (AD), which is characterized by progressive cognitive decline that correlates with the spread of tau protein aggregation in the cortical mantle, is strongly age-related. It could be that age predisposes the brain for tau misfolding and supports the propagation of tau pathology. We tested this hypothesis using an experimental setup that allowed for exploration of age-related factors of tau spread and regional vulnerability. We virally expressed human tau locally in entorhinal cortex (EC) neurons of young or old mice and monitored the cell-to-cell tau protein spread by immunolabeling. Old animals showed more tau spreading in the hippocampus and adjacent cortical areas and accumulated more misfolded tau in EC neurons. No misfolding, at any age, was observed in the striatum, a brain region mostly unaffected by tangles. Age and brain region dependent tau spreading and misfolding likely contribute to the profound age-related risk for sporadic AD.
- Published
- 2019
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26. The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques.
- Author
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Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, Mancuso R, Chen WT, Woodbury ME, Srivastava G, Möller T, Hudry E, Das S, Saido T, Karran E, Hyman B, Perry VH, Fiers M, and De Strooper B
- Subjects
- Aging genetics, Aging metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor physiology, Animals, Biomarkers analysis, Brain metabolism, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, ApoE, Mice, Transgenic, Microglia metabolism, Plaque, Amyloid genetics, Plaque, Amyloid metabolism, Presenilins physiology, Sex Characteristics, Aging pathology, Alzheimer Disease pathology, Biomarkers metabolism, Brain pathology, Disease Models, Animal, Microglia pathology, Plaque, Amyloid pathology
- Abstract
Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus of male and female App
NL-G-F mice over time demonstrate that progressive amyloid-β accumulation accelerates two main activated microglia states that are also present during normal aging. Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1) and are strongly enriched with Alzheimer's disease (AD) risk genes. Microglia from female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. Apoe, the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia (IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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27. Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality.
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Hudry E and Vandenberghe LH
- Published
- 2019
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28. Opposing Roles of apolipoprotein E in aging and neurodegeneration.
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Hudry E, Klickstein J, Cannavo C, Jackson R, Muzikansky A, Gandhi S, Urick D, Sargent T, Wrobleski L, Roe AD, Hou SS, Kuchibhotla KV, Betensky RA, Spires-Jones T, and Hyman BT
- Subjects
- Alzheimer Disease genetics, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloidosis, Animals, Disease Models, Animal, Evoked Potentials, Visual genetics, Humans, Loss of Function Mutation genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neuroglia metabolism, Neurons metabolism, Plaque, Amyloid pathology, Presenilin-1 genetics, Synapses metabolism, Aging physiology, Apolipoproteins E genetics, Regeneration physiology, Visual Cortex physiology
- Abstract
Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer's disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/PSEN1 mice (8-10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18-20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE's role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging., (© 2019 Hudry et al.)
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- 2019
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29. Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain.
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Hopp SC, Bihlmeyer NA, Corradi JP, Vanderburg C, Cacace AM, Das S, Clark TW, Betensky RA, Hyman BT, and Hudry E
- Subjects
- Alzheimer Disease pathology, Animals, Computational Biology, Gene Expression Regulation, Genetic Vectors administration & dosage, Genetic Vectors genetics, Hippocampus, Male, Mice, Mice, Inbred C57BL, NFATC Transcription Factors genetics, NFATC Transcription Factors metabolism, Neurons pathology, RNA, Messenger biosynthesis, RNA, Messenger genetics, Synapses metabolism, Transcriptional Activation, Alzheimer Disease genetics, Calcineurin genetics, Neurons metabolism
- Abstract
Synaptic dysfunction and loss are core pathological features in Alzheimer disease (AD). In the vicinity of amyloid-β plaques in animal models, synaptic toxicity occurs and is associated with chronic activation of the phosphatase calcineurin (CN). Indeed, pharmacological inhibition of CN blocks amyloid-β synaptotoxicity. We therefore hypothesized that CN-mediated transcriptional changes may contribute to AD neuropathology and tested this by examining the impact of CN over-expression on neuronal gene expression in vivo. We found dramatic transcriptional down-regulation, especially of synaptic mRNAs, in neurons chronically exposed to CN activation. Importantly, the transcriptional profile parallels the changes in human AD tissue. Bioinformatics analyses suggest that both nuclear factor of activated T cells and numerous microRNAs may all be impacted by CN, and parallel findings are observed in AD. These data and analyses support the hypothesis that at least part of the synaptic failure characterizing AD may result from aberrant CN activation leading to down-regulation of synaptic genes, potentially via activation of specific transcription factors and expression of repressive microRNAs., Open Practices: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Read the Editorial Highlight for this article on page 8., (© 2018 International Society for Neurochemistry.)
- Published
- 2018
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30. Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery.
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Volak A, LeRoy SG, Natasan JS, Park DJ, Cheah PS, Maus A, Fitzpatrick Z, Hudry E, Pinkham K, Gandhi S, Hyman BT, Mu D, GuhaSarkar D, Stemmer-Rachamimov AO, Sena-Esteves M, Badr CE, and Maguire CA
- Subjects
- Animals, Astrocytes cytology, Brain Neoplasms genetics, Brain Neoplasms pathology, Disease Models, Animal, Female, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Nude, Promoter Regions, Genetic, Stromal Cells cytology, Astrocytes metabolism, Brain Neoplasms therapy, Dependovirus genetics, Genetic Therapy, Interferon-beta genetics, Stromal Cells metabolism
- Abstract
The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-κB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ.
- Published
- 2018
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31. A flow cytometry-based in vitro assay reveals that formation of apolipoprotein E (ApoE)-amyloid beta complexes depends on ApoE isoform and cell type.
- Author
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Kara E, Marks JD, Roe AD, Commins C, Fan Z, Calvo-Rodriguez M, Wegmann S, Hudry E, and Hyman BT
- Subjects
- Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Astrocytes cytology, Biological Assay, Cell Lineage, HEK293 Cells, Humans, In Vitro Techniques, Male, Mice, Mice, Transgenic, Neurons cytology, Protein Isoforms, Amyloid beta-Peptides metabolism, Apolipoprotein E2 metabolism, Apolipoprotein E3 metabolism, Apolipoprotein E4 metabolism, Astrocytes metabolism, Flow Cytometry methods, Neurons metabolism
- Abstract
Apolipoprotein E (ApoE) is a secreted apolipoprotein with three isoforms, E2, E3, and E4, that binds to lipids and facilitates their transport in the extracellular environment of the brain and the periphery. The E4 allele is a major genetic risk factor for the sporadic form of Alzheimer's disease (AD), and studies of human brain and mouse models have revealed that E4 significantly exacerbates the deposition of amyloid beta (Aβ). It has been suggested that this deposition could be attributed to the formation of soluble ApoE isoform-specific ApoE-Aβ complexes. However, previous studies have reported conflicting results regarding the directionality and strength of those interactions. In this study, using a series of flow cytometry assays that maintain the physiological integrity of ApoE-Aβ complexes, we systematically assessed the association of Aβ with ApoE2, E3, or E4. We used ApoE secreted from HEK cells or astrocytes overexpressing ApoE fused with a GFP tag. As a source of soluble Aβ peptide, we used synthetic Aβ40 or Aβ42 or physiological Aβ secreted from CHO cell lines overexpressing WT or V717F variant amyloid precursor protein (APP). We observed significant interactions between the different ApoE isoforms and Aβ, with E4 interacting with Aβ more strongly than the E2 and E3 isoforms. We also found subtle differences depending on the Aβ type and the ApoE-producing cell type. In conclusion, these results indicate that the strength of the ApoE-Aβ association depends on the source of Aβ or ApoE., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2018
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32. Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65.
- Author
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Hudry E, Andres-Mateos E, Lerner EP, Volak A, Cohen O, Hyman BT, Maguire CA, and Vandenberghe LH
- Abstract
Adeno-associated viral vectors (AAVs) have demonstrated potential in applications for neurologic disorders, and the discovery that some AAVs can cross the blood-brain barrier (BBB) after intravenous injection has further expanded these opportunities for non-invasive brain delivery. Anc80L65, a novel AAV capsid designed from in silico reconstruction of the viral evolutionary lineage, has previously demonstrated robust transduction capabilities after local delivery in various tissues such as liver, retina, or cochlea, compared with conventional AAVs. Here, we compared the transduction efficacy of Anc80L65 with conventional AAV9 in the CNS after intravenous, intracerebroventricular (i.c.v.), or intraparenchymal injections. Anc80L65 was more potent at targeting the brain and spinal cord after intravenous injection than AAV9, and mostly transduced astrocytes and a wide range of neuronal subpopulations. Although the efficacy of Anc80L65 and AAV9 is similar after direct intraparenchymal injection in the striatum, Anc80L65's diffusion throughout the CNS was more extensive than AAV9 after i.c.v. infusion, leading to widespread EGFP expression in the cerebellum. These findings demonstrate that Anc80L65 is a highly efficient gene transfer vector for the murine CNS. Systemic injection of Anc80L65 leads to notable expression in the CNS that does not rely on a self-complementary genome. These data warrant further testing in larger animal models.
- Published
- 2018
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33. In Vivo Two Photon Imaging of Astrocytic Structure and Function in Alzheimer's Disease.
- Author
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Kelly P, Hudry E, Hou SS, and Bacskai BJ
- Abstract
The physiological function of the neurovascular unit is critically dependent upon the complex structure and functions of astrocytes for optimal preservation of cerebral homeostasis. While it has been shown that astrocytes exhibit aberrant changes in both structure and function in transgenic murine models of Alzheimer's disease (AD), it is not fully understood how this altered phenotype contributes to the pathogenesis of AD or whether this alteration predicts a therapeutic target in AD. The mechanisms underlying the spatiotemporal relationship between astrocytes, neurons and the vasculature in their orchestrated regulation of local cerebral flow in active brain regions has not been fully elucidated in brain physiology and in AD. As there is an incredible urgency to identify therapeutic targets that are well-tolerated and efficacious in protecting the brain against the pathological impact of AD, here we use the current body of literature to evaluate the hypothesis that pathological changes in astrocytes are central to the pathogenesis of AD. We also examine the current tools available to assess astrocytic calcium signaling in the living murine brain as it has an important role in the complex interaction between astrocytes, neurons and the vasculature. Furthermore, we discuss the altered function of astrocytes in their interaction with neurons in the preservation of glutamate homeostasis and additionally address the role of astrocytes at the vascular interface and their contribution to functional hyperemia within the living murine brain in health and in AD.
- Published
- 2018
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34. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation.
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Liao F, Li A, Xiong M, Bien-Ly N, Jiang H, Zhang Y, Finn MB, Hoyle R, Keyser J, Lefton KB, Robinson GO, Serrano JR, Silverman AP, Guo JL, Getz J, Henne K, Leyns CE, Gallardo G, Ulrich JD, Sullivan PM, Lerner EP, Hudry E, Sweeney ZK, Dennis MS, Hyman BT, Watts RJ, and Holtzman DM
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Animals, Apolipoprotein E3 antagonists & inhibitors, Apolipoprotein E3 genetics, Apolipoprotein E3 metabolism, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Humans, Mice, Mice, Knockout, Plaque, Amyloid genetics, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Alzheimer Disease drug therapy, Amyloid beta-Peptides metabolism, Antibodies, Monoclonal, Murine-Derived pharmacology, Apolipoprotein E4 antagonists & inhibitors, Plaque, Amyloid drug therapy
- Abstract
The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aβ deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aβ pathology and may represent a selective approach to treat AD.
- Published
- 2018
- Full Text
- View/download PDF
35. Cromolyn Reduces Levels of the Alzheimer's Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis.
- Author
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Zhang C, Griciuc A, Hudry E, Wan Y, Quinti L, Ward J, Forte AM, Shen X, Ran C, Elmaleh DR, and Tanzi RE
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides biosynthesis, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Anti-Asthmatic Agents pharmacology, Brain drug effects, Brain metabolism, Brain pathology, Disease Models, Animal, Drug Combinations, Drug Repositioning, Gene Expression, Humans, Male, Mice, Mice, Transgenic, Microglia cytology, Microglia metabolism, Neurons drug effects, Neurons metabolism, Neurons pathology, Peptide Fragments antagonists & inhibitors, Peptide Fragments biosynthesis, Phagocytosis drug effects, Transgenes, Alzheimer Disease drug therapy, Amyloid beta-Protein Precursor antagonists & inhibitors, Cromolyn Sodium pharmacology, Ibuprofen pharmacology, Microglia drug effects, Neuroprotective Agents pharmacology
- Abstract
Amyloid-beta protein (Aβ) deposition is a pathological hallmark of Alzheimer's disease (AD). Aβ deposition triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium is an asthma therapeutic agent previously shown to reduce Aβ levels in transgenic AD mouse brains after one-week of treatment. Here, we further explored these effects as well as the mechanism of action of cromolyn, alone, and in combination with ibuprofen in APP
Swedish -expressing Tg2576 mice. Mice were treated for 3 months starting at 5 months of age, when the earliest stages of β-amyloid deposition begin. Cromolyn, alone, or in combination with ibuprofen, almost completely abolished longer insoluble Aβ species, i.e. Aβ40 and Aβ42, but increased insoluble Aβ38 levels. In addition to its anti-aggregation effects on Aβ, cromolyn, alone, or plus ibuprofen, but not ibuprofen alone, increased microglial recruitment to, and phagocytosis of β-amyloid deposits in AD mice. Cromolyn also promoted Aβ42 uptake in microglial cell-based assays. Collectively, our data reveal robust effects of cromolyn, alone, or in combination with ibuprofen, in reducing aggregation-prone Aβ levels and inducing a neuroprotective microglial activation state favoring Aβ phagocytosis versus a pro-neuroinflammatory state. These findings support the use of cromolyn, alone, or with ibuprofen, as a potential AD therapeutic.- Published
- 2018
- Full Text
- View/download PDF
36. Isoform- and cell type-specific structure of apolipoprotein E lipoparticles as revealed by a novel Forster resonance energy transfer assay.
- Author
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Kara E, Marks JD, Fan Z, Klickstein JA, Roe AD, Krogh KA, Wegmann S, Maesako M, Luo CC, Mylvaganam R, Berezovska O, Hudry E, and Hyman BT
- Subjects
- Apolipoproteins E metabolism, Flow Cytometry, HEK293 Cells, Humans, Protein Conformation, Protein Isoforms chemistry, Protein Isoforms metabolism, Apolipoproteins E chemistry, Astrocytes chemistry, Fluorescence Resonance Energy Transfer
- Abstract
Apolipoprotein E (apoE) has an important role in the pathogenesis of Alzheimer's disease with its three isoforms having distinct effects on disease risk. Here, we assessed the conformational differences between those isoforms using a novel flow cytometry-Forster resonance energy transfer (FRET) assay. We showed that the conformation of intracellular apoE within HEK cells and astrocytes adopts a directional pattern; in other words, E4 adopts the most closed conformation, E2 adopts the most open conformation, and E3 adopts an intermediate conformation. However, this pattern was not maintained upon secretion of apoE from astrocytes. Intermolecular interactions between apoE molecules were isoform-specific, indicating a great diversity in the structure of apoE lipoparticles. Finally, we showed that secreted E4 is the most lipidated isoform in astrocytes, suggesting that increased lipidation acts as a folding chaperone enabling E4 to adopt a closed conformation. In conclusion, this study gives insights into apoE biology and establishes a robust screening system to monitor apoE conformation., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
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37. Neuronal Cholesterol Accumulation Induced by Cyp46a1 Down-Regulation in Mouse Hippocampus Disrupts Brain Lipid Homeostasis.
- Author
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Ayciriex S, Djelti F, Alves S, Regazzetti A, Gaudin M, Varin J, Langui D, Bièche I, Hudry E, Dargère D, Aubourg P, Auzeil N, Laprévote O, and Cartier N
- Abstract
Impairment in cholesterol metabolism is associated with many neurodegenerative disorders including Alzheimer's disease (AD). However, the lipid alterations underlying neurodegeneration and the connection between altered cholesterol levels and AD remains not fully understood. We recently showed that cholesterol accumulation in hippocampal neurons, induced by silencing Cyp46a1 gene expression, leads to neurodegeneration with a progressive neuronal loss associated with AD-like phenotype in wild-type mice. We used a targeted and non-targeted lipidomics approach by liquid chromatography coupled to high-resolution mass spectrometry to further characterize lipid modifications associated to neurodegeneration and cholesterol accumulation induced by CYP46A1 inhibition. Hippocampus lipidome of normal mice was profiled 4 weeks after cholesterol accumulation due to Cyp46a1 gene expression down-regulation at the onset of neurodegeneration. We showed that major membrane lipids, sphingolipids and specific enzymes involved in phosphatidylcholine and sphingolipid metabolism, were rapidly increased in the hippocampus of AAV-shCYP46A1 injected mice. This lipid accumulation was associated with alterations in the lysosomal cargoe, accumulation of phagolysosomes and impairment of endosome-lysosome trafficking. Altogether, we demonstrated that inhibition of cholesterol 24-hydroxylase, key enzyme of cholesterol metabolism leads to a complex dysregulation of lipid homeostasis. Our results contribute to dissect the potential role of lipids in severe neurodegenerative diseases like AD.
- Published
- 2017
- Full Text
- View/download PDF
38. Viral vectors for therapy of neurologic diseases.
- Author
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Choudhury SR, Hudry E, Maguire CA, Sena-Esteves M, Breakefield XO, and Grandi P
- Subjects
- Animals, Brain Neoplasms therapy, Gene Transfer Techniques, Genetic Vectors physiology, Humans, Genetic Therapy methods, Genetic Vectors therapeutic use, Nervous System Diseases therapy
- Abstract
Neurological disorders - disorders of the brain, spine and associated nerves - are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches - pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others - have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors - encoding a therapeutic gene or inhibitory RNA into a "gutted" viral capsid and supplying it to the nervous system - has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders"., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
39. Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain.
- Author
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Arbel-Ornath M, Hudry E, Boivin JR, Hashimoto T, Takeda S, Kuchibhotla KV, Hou S, Lattarulo CR, Belcher AM, Shakerdge N, Trujillo PB, Muzikansky A, Betensky RA, Hyman BT, and Bacskai BJ
- Subjects
- Amyloid beta-Peptides metabolism, Animals, Calcium Signaling physiology, Disease Models, Animal, Humans, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Synapses drug effects, Alzheimer Disease physiopathology, Amyloid beta-Peptides toxicity, Brain physiopathology, Calcium Signaling drug effects, Synapses pathology
- Abstract
Background: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer's disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes., Method: To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging., Results: We observed a dramatic increase in the levels of neuronal resting calcium, which was dependent upon extracellular calcium influx and activation of NMDA receptors. Ryanodine receptors, previously implicated in AD models, did not appear to be primarily involved using this experimental setting. We used the high resolution cortical volumes acquired in-vivo to measure the effect on synaptic densities and observed that, while spine density remained stable within the first hour of oAβ exposure, a significant decrease in the number of dendritic spines was observed 24 h post treatment, despite restoration of intraneuronal calcium levels at this time point., Conclusions: These observations demonstrate a specific effect of oAβ on NMDA-mediated calcium influx, which triggers synaptic collapse in vivo. Moreover, this work leverages a method to quantitatively measure calcium concentration at the level of neuronal processes, cell bodies and single synaptic elements repeatedly and thus can be applicable to testing putative drugs and/or other intervention methodologies.
- Published
- 2017
- Full Text
- View/download PDF
40. New Therapeutic Avenue for ALS: Avoiding a Fatal Encounter of TDP-43 at the Mitochondria.
- Author
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Hudry E
- Subjects
- Humans, Mitochondria, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins
- Published
- 2017
- Full Text
- View/download PDF
41. Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells.
- Author
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Merkel SF, Andrews AM, Lutton EM, Mu D, Hudry E, Hyman BT, Maguire CA, and Ramirez SH
- Subjects
- Blood-Brain Barrier cytology, Brain metabolism, Cells, Cultured, Humans, Transcytosis physiology, Blood-Brain Barrier virology, Brain virology, Cell Movement physiology, Dependovirus, Endothelial Cells virology, Tight Junctions virology
- Abstract
Developing therapies for central nervous system (CNS) diseases is exceedingly difficult because of the blood-brain barrier (BBB). Notably, emerging technologies may provide promising new options for the treatment of CNS disorders. Adeno-associated virus serotype 9 (AAV9) has been shown to transduce cells in the CNS following intravascular administration in rodents, cats, pigs, and non-human primates. These results suggest that AAV9 is capable of crossing the BBB. However, mechanisms that govern AAV9 transendothelial trafficking at the BBB remain unknown. Furthermore, possibilities that AAV9 may transduce brain endothelial cells or affect BBB integrity still require investigation. Using primary human brain microvascular endothelial cells as a model of the human BBB, we performed transduction and transendothelial trafficking assays comparing AAV9 to AAV2, a serotype that does not cross the BBB or transduce endothelial cells effectively in vivo. Results of our in vitro studies indicate that AAV9 penetrates brain microvascular endothelial cells barriers more effectively than AAV2, but has reduced transduction efficiency. In addition, our data suggest that (i) AAV9 penetrates endothelial barriers through an active, cell-mediated process, and (ii) AAV9 fails to disrupt indicators of BBB integrity such as transendothelial electrical resistance, tight junction protein expression/localization, and inflammatory activation status. Overall, this report shows how human brain endothelial cells configured in BBB models can be utilized for evaluating transendothelial movement and transduction kinetics of various AAV capsids. Importantly, the use of a human in vitro BBB model can provide import insight into the possible effects that candidate AVV gene therapy vectors may have on the status of BBB integrity. Read the Editorial Highlight for this article on page 192., Competing Interests: The authors declare no competing financial interests., (© 2016 International Society for Neurochemistry.)
- Published
- 2017
- Full Text
- View/download PDF
42. Tailored transgene expression to specific cell types in the central nervous system after peripheral injection with AAV9.
- Author
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Dashkoff J, Lerner EP, Truong N, Klickstein JA, Fan Z, Mu D, Maguire CA, Hyman BT, and Hudry E
- Abstract
The capacity of certain adeno-associated virus (AAV) vectors to cross the blood-brain barrier after intravenous delivery offers a unique opportunity for noninvasive brain delivery. However, without a well-tailored system, the use of a peripheral route injection may lead to undesirable transgene expression in nontarget cells or organs. To refine this approach, the present study characterizes the transduction profiles of new self-complementary AAV9 (scAAV9) expressing the green fluorescent protein (GFP) either under an astrocyte (glial fibrillary acidic (GFA) protein) or neuronal (Synapsin (Syn)) promoter, after intravenous injection of adult mice (2 × 10
13 vg/kg). ScAAV9-GFA-GFP and scAAV9-Syn-GFP robustly transduce astrocytes (11%) and neurons (17%), respectively, without aberrant expression leakage. Interestingly, while the percentages of GFP-positive astrocytes with scAAV9-GFA-GFP are similar to the performances observed with scAAV9-CBA-GFP (broadly active promoter), significant higher percentages of neurons express GFP with scAAV9-Syn-GFP. GFP-positive excitatory as well as inhibitory neurons are observed, as well as motor neurons in the spinal cord. Additionally, both activated (GFAP-positive) and resting astrocytes (GFAP-negative) express the reporter gene after scAAV9-GFA-GFP injection. These data thoroughly characterize the gene expression specificity of AAVs fitted with neuronal and astrocyte-selective promoters after intravenous delivery, which will prove useful for central nervous system (CNS) gene therapy approaches in which peripheral expression of transgene is a concern.- Published
- 2016
- Full Text
- View/download PDF
43. Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques.
- Author
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Galea E, Morrison W, Hudry E, Arbel-Ornath M, Bacskai BJ, Gómez-Isla T, Stanley HE, and Hyman BT
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Animals, Astrocytes pathology, Biophysical Phenomena, Cell Movement, Computer Simulation, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Mutant Strains, Mice, Transgenic, Microscopy, Fluorescence, Multiphoton, Models, Neurological, Plaque, Amyloid pathology, Recombinant Proteins genetics, Recombinant Proteins metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Astrocytes physiology, Plaque, Amyloid metabolism, Presenilin-1 genetics, Presenilin-1 metabolism
- Abstract
Although the clustering of GFAP immunopositive astrocytes around amyloid-β plaques in Alzheimer's disease has led to the widespread assumption that plaques attract astrocytes, recent studies suggest that astrocytes stay put in injury. Here we reexamine astrocyte migration to plaques, using quantitative spatial analysis and computer modeling to investigate the topology of astrocytes in 3D images obtained by two-photon microscopy of living APP/PS1 mice and WT littermates. In WT mice, cortical astrocyte topology fits a model in which a liquid of hard spheres exclude each other in a confined space. Plaques do not disturb this arrangement except at very large plaque loads, but, locally, cause subtle outward shifts of the astrocytes located in three tiers around plaques. These data suggest that astrocytes respond to plaque-induced neuropil injury primarily by changing phenotype, and hence function, rather than location.
- Published
- 2015
- Full Text
- View/download PDF
44. Massachusetts Alzheimer's Disease Research Center: progress and challenges.
- Author
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Hyman BT, Growdon JH, Albers MW, Buckner RL, Chhatwal J, Gomez-Isla MT, Haass C, Hudry E, Jack CR Jr, Johnson KA, Khachaturian ZS, Kim DY, Martin JB, Nitsch RM, Rosen BR, Selkoe DJ, Sperling RA, St George-Hyslop P, Tanzi RE, Yap L, Young AB, Phelps CH, and McCaffrey PG
- Subjects
- Biomarkers, Clinical Trials as Topic, Humans, Massachusetts, Neuroimaging, Alzheimer Disease diagnosis, Alzheimer Disease genetics, Biomedical Research organization & administration
- Published
- 2015
- Full Text
- View/download PDF
45. Abnormal synaptic Ca(2+) homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice.
- Author
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Eikermann-Haerter K, Arbel-Ornath M, Yalcin N, Yu ES, Kuchibhotla KV, Yuzawa I, Hudry E, Willard CR, Climov M, Keles F, Belcher AM, Sengul B, Negro A, Rosen IA, Arreguin A, Ferrari MD, van den Maagdenberg AM, Bacskai BJ, and Ayata C
- Subjects
- Animals, Calcium Channels, N-Type metabolism, Calcium-Transporting ATPases antagonists & inhibitors, Cerebral Cortex cytology, Cerebral Cortex drug effects, Cortical Spreading Depression drug effects, Disease Models, Animal, Enzyme Inhibitors pharmacology, Homeostasis genetics, Hydroquinones pharmacology, Mice, Microscopy, Fluorescence, Multiphoton, Migraine with Aura genetics, Migraine with Aura pathology, Mutation, Neurons drug effects, Neurons pathology, Synapses drug effects, Synapses pathology, Calcium metabolism, Calcium Channels, N-Type genetics, Cerebral Cortex metabolism, Cortical Spreading Depression genetics, Migraine with Aura metabolism, Neurons metabolism, Synapses metabolism
- Abstract
Objective: Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV 2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV 2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear., Methods: We employed in vivo multiphoton microscopy of the genetically encoded Ca(2+)-indicator yellow cameleon to investigate synaptic morphology and [Ca(2+)]i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the CaV 2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo., Results: FHM1 mutations elevate neuronal [Ca(2+)]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV 2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca(2+)]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca(2+)]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains., Interpretation: Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca(2+) homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs., (© 2015 American Neurological Association.)
- Published
- 2015
- Full Text
- View/download PDF
46. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease.
- Author
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Djelti F, Braudeau J, Hudry E, Dhenain M, Varin J, Bièche I, Marquer C, Chali F, Ayciriex S, Auzeil N, Alves S, Langui D, Potier MC, Laprevote O, Vidaud M, Duyckaerts C, Miles R, Aubourg P, and Cartier N
- Subjects
- Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Animals, Cholesterol 24-Hydroxylase, Female, Homeostasis physiology, Mice, Inbred C57BL, Mice, Transgenic, Neurons metabolism, Alzheimer Disease metabolism, Brain metabolism, Cholesterol metabolism, Enzyme Inhibitors pharmacology, Steroid Hydroxylases antagonists & inhibitors
- Abstract
Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
- View/download PDF
47. A Food and Drug Administration-approved asthma therapeutic agent impacts amyloid β in the brain in a transgenic model of Alzheimer disease.
- Author
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Hori Y, Takeda S, Cho H, Wegmann S, Shoup TM, Takahashi K, Irimia D, Elmaleh DR, Hyman BT, and Hudry E
- Subjects
- Animals, Cells, Cultured, Cromolyn Sodium chemistry, Disease Models, Animal, Flavonoids chemistry, Flavonols, Humans, Mice, Mice, Transgenic, Microglia metabolism, Microscopy, Electron, Transmission, United States, United States Food and Drug Administration, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Brain metabolism, Cromolyn Sodium pharmacology, Drug Approval, Peptide Fragments metabolism
- Abstract
Interfering with the assembly of Amyloid β (Aβ) peptides from monomer to oligomeric species and fibrils or promoting their clearance from the brain are targets of anti-Aβ-directed therapies in Alzheimer disease. Here we demonstrate that cromolyn sodium (disodium cromoglycate), a Food and Drug Administration-approved drug already in use for the treatment of asthma, efficiently inhibits the aggregation of Aβ monomers into higher-order oligomers and fibrils in vitro without affecting Aβ production. In vivo, the levels of soluble Aβ are decreased by over 50% after only 1 week of daily intraperitoneally administered cromolyn sodium. Additional in vivo microdialysis studies also show that this compound decreases the half-life of soluble Aβ in the brain. These data suggest a clear effect of a peripherally administered, Food and Drug Administration-approved medication on Aβ economy, supporting further investigation of the potential long-term efficacy of cromolyn sodium in Alzheimer disease., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
48. Anti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis.
- Author
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Liao F, Hori Y, Hudry E, Bauer AQ, Jiang H, Mahan TE, Lefton KB, Zhang TJ, Dearborn JT, Kim J, Culver JP, Betensky R, Wozniak DF, Hyman BT, and Holtzman DM
- Subjects
- Alzheimer Disease blood, Alzheimer Disease genetics, Amyloid beta-Peptides drug effects, Amyloid beta-Protein Precursor genetics, Amyloidosis drug therapy, Amyloidosis metabolism, Amyloidosis pathology, Animals, Brain drug effects, Cholesterol blood, Disease Models, Animal, Female, Hemorrhage drug therapy, Hemorrhage etiology, Lameness, Animal drug therapy, Lameness, Animal etiology, Maze Learning drug effects, Maze Learning physiology, Mice, Mice, Transgenic, Mutation genetics, Presenilin-1 genetics, Alzheimer Disease drug therapy, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Antibodies therapeutic use, Apolipoproteins E immunology, Brain metabolism
- Abstract
Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology., (Copyright © 2014 the authors 0270-6474/14/347281-12$15.00/0.)
- Published
- 2014
- Full Text
- View/download PDF
49. RNA aptamer probes as optical imaging agents for the detection of amyloid plaques.
- Author
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Farrar CT, William CM, Hudry E, Hashimoto T, and Hyman BT
- Subjects
- Alzheimer Disease pathology, Animals, Base Pairing, Base Sequence, Blotting, Western, Humans, Immunoblotting, Mice, Mice, Transgenic, Molecular Sequence Data, Alzheimer Disease diagnosis, Aptamers, Nucleotide genetics, Optical Imaging methods, Plaque, Amyloid ultrastructure, RNA Probes genetics
- Abstract
Optical imaging using multiphoton microscopy and whole body near infrared imaging has become a routine part of biomedical research. However, optical imaging methods rely on the availability of either small molecule reporters or genetically encoded fluorescent proteins, which are challenging and time consuming to develop. While directly labeled antibodies can also be used as imaging agents, antibodies are species specific, can typically not be tagged with multiple fluorescent reporters without interfering with target binding, and are bioactive, almost always eliciting a biological response and thereby influencing the process that is being studied. We examined the possibility of developing highly specific and sensitive optical imaging agents using aptamer technology. We developed a fluorescently tagged anti-Aβ RNA aptamer, β55, which binds amyloid plaques in both ex vivo human Alzheimer's disease brain tissue and in vivo APP/PS1 transgenic mice. Diffuse β55 positive halos, attributed to oligomeric Aβ, were observed surrounding the methoxy-XO4 positive plaque cores. Dot blots of synthetic Aβ aggregates provide further evidence that β55 binds both fibrillar and non-fibrillar Aβ. The high binding affinity, the ease of probe development, and the ability to incorporate multiple and multimodal imaging reporters suggest that RNA aptamers may have complementary and perhaps advantageous properties compared to conventional optical imaging probes and reporters.
- Published
- 2014
- Full Text
- View/download PDF
50. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain.
- Author
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Hudry E, Dashkoff J, Roe AD, Takeda S, Koffie RM, Hashimoto T, Scheel M, Spires-Jones T, Arbel-Ornath M, Betensky R, Davidson BL, and Hyman BT
- Subjects
- Amyloid toxicity, Animals, Apolipoproteins E administration & dosage, Humans, Injections, Intraventricular, Mice, Mice, Transgenic, Amyloid metabolism, Apolipoproteins E genetics, Brain metabolism, Transfection
- Abstract
Inheritance of the ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor associated with the sporadic form of Alzheimer's disease (AD), whereas the rare APOE ε2 allele has the opposite effect. However, the mechanisms whereby APOE confers risk and protection remain uncertain. We used a gene transfer approach to bathe the cortex of amyloid plaque-bearing transgenic mice with virally expressed human APOE. We monitored amyloid-β (Aβ) with multiphoton imaging, in vivo microdialysis, and postmortem array tomography to study the kinetics of human APOE-mediated changes in Aβ-related neurotoxicity in a mouse model of AD. We observed that human APOE4 increased the concentrations of oligomeric Aβ within the interstitial fluid and exacerbated plaque deposition; the converse occurred after exposure to human APOE2. Peri-plaque synapse loss and dystrophic neurites were also worsened by APOE4 or attenuated by APOE2. Egress of Aβ from the central nervous system (CNS) into the plasma was diminished by APOE3 and APOE4 compared to APOE2, in accord with isoform-specific retention of Aβ in the CNS. Overall, our data show a differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Aβ-mediated synaptotoxicity. These results suggest that the APOE genetic risk is mediated by Aβ, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD.
- Published
- 2013
- Full Text
- View/download PDF
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