21 results on '"Zehr C"'
Search Results
2. In vivo silencing of alpha-synuclein using naked siRNA
- Author
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Lewis, J., Melrose, H., Bumcrot, D., Hope, A., Zehr, C., Lincoln, S., Braithwaite, A., He, Z., Ogholikhan, S., and Hinkle, K.
- Published
- 2008
3. Studentsʼ use of anatomy modules in problem-based medical education at McMaster University
- Author
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Zehr, C L, primary, Butler, R G, additional, and Richardson, R J, additional
- Published
- 1996
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4. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families
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Clark, R.F., primary, Hutton, M., additional, Fuldner, M., additional, Froelich, S., additional, Karran, E., additional, Talbot, C., additional, Crook, R., additional, Lendon, C., additional, Prihar, G., additional, He, C., additional, Korenblat, K., additional, Martinez, A., additional, Wragg, M., additional, Busfield, F., additional, Behrens, M.I., additional, Myers, A., additional, Norton, J., additional, Morris, J., additional, Mehta, N., additional, Pearson, C., additional, Lincoln, S., additional, Baker, M., additional, Duff, K., additional, Zehr, C., additional, Perez-Tur, J., additional, Houlden, H., additional, Ruiz, A., additional, Ossa, J., additional, Lopera, F., additional, Arcos, M., additional, Madrigal, L., additional, Collinge, J., additional, Humphreys, C., additional, Ashworth, A., additional, Sarner, S., additional, Fox, N., additional, Harvey, R., additional, Kennedy, A., additional, Roques, P., additional, Cline, R.T., additional, Philips, C.A., additional, Venter, J.C., additional, Forsell, L., additional, Axelman, K., additional, Lilius, L., additional, Johnston, J., additional, Cowburn, R., additional, Viitanen, M., additional, Winblad, B., additional, Kosik, K., additional, Haltia, M., additional, Poyhonen, M., additional, Dickson, D., additional, Mann, D., additional, Neary, D., additional, Snowden, J., additional, Lantos, P., additional, Lannfelt, L., additional, Rossor, M., additional, Roberts, G.W., additional, Adams, M.D., additional, Hardy, J., additional, and Goate, A., additional
- Published
- 1995
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- View/download PDF
5. In vivo silencing of alpha-synuclein using naked siRNA
- Author
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Charisse Klaus, Toudjarska Ivanka, Kent Caroline, Hinkle Kelly, Ogholikhan Sina, He Zhen, Braithwaite Adam, Lincoln Sarah, Zehr Cynthia, Hope Andrew, Bumcrot David, Melrose Heather, Lewis Jada, Braich Ravi, Pandey Rajendra K, Heckman Michael, Maraganore Demetrius M, Crook Julia, and Farrer Matthew J
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. Results We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion. Conclusion We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression.
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- 2008
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6. Implementation intentions for physical activity behavior in older adult women: an examination of executive function as a moderator of treatment effects.
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Hall PA, Zehr C, Paulitzki J, and Rhodes R
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- Accelerometry, Aged, Aged, 80 and over, Female, Humans, Middle Aged, Program Evaluation, Self Report, Executive Function, Health Behavior, Intention, Motor Activity
- Abstract
Background: Implementation intentions are effective for enhancing physical activity, but it is unknown how well these effects extend to older adults and/or are modified by cognitive variables., Purpose: Our objective is to examine (1) the efficacy of an implementation intentions intervention for physical activity in older adult women and (2) to examine the moderating effects of executive function., Methods: Participants (N = 75, M age = 73.72) completed measures of executive function and were randomly assigned to weekly implementation intentions for physical activity (experimental condition), implementation intentions for an unrelated behavior (control condition), or no treatment. Baseline activity was measured by accelerometer and self-report; follow-up activity was measured by weekly self-report., Results: Findings indicated a significant treatment effect for the experimental condition and a treatment by executive function interaction. Specifically, participants with relatively stronger executive function benefited most from the experimental intervention., Conclusions: Implementation intentions are effective for enhancing physical activity among older adult women, and the effects may be especially pronounced for those with relatively stronger executive function.
- Published
- 2014
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7. In vivo silencing of alpha-synuclein using naked siRNA.
- Author
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Lewis J, Melrose H, Bumcrot D, Hope A, Zehr C, Lincoln S, Braithwaite A, He Z, Ogholikhan S, Hinkle K, Kent C, Toudjarska I, Charisse K, Braich R, Pandey RK, Heckman M, Maraganore DM, Crook J, and Farrer MJ
- Abstract
Background: Overexpression of alpha-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD., Results: We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion., Conclusion: We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for alpha-synucleinopathies resulting from SNCA overexpression.
- Published
- 2008
- Full Text
- View/download PDF
8. In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons.
- Author
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Spires-Jones TL, de Calignon A, Matsui T, Zehr C, Pitstick R, Wu HY, Osetek JD, Jones PB, Bacskai BJ, Feany MB, Carlson GA, Ashe KH, Lewis J, and Hyman BT
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- Animals, Caspases analysis, Cell Death physiology, Enzyme Activation physiology, Humans, Mice, Mice, Transgenic, Microscopy, Fluorescence, Multiphoton, Neurofibrillary Tangles chemistry, Neurofibrillary Tangles pathology, Neurons chemistry, Neurons pathology, tau Proteins metabolism, tau Proteins physiology, Apoptosis physiology, Caspases metabolism, Neurofibrillary Tangles enzymology, Neurons enzymology
- Abstract
Accumulation of neurofibrillary tangles (NFTs) in Alzheimer's disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.
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- 2008
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9. Biologic models of neurodegenerative disorders.
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Eriksen JL, Zehr C, and Lewis J
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- Animals, Brain metabolism, Brain pathology, Humans, Peptides genetics, Peptides metabolism, alpha-Synuclein genetics, alpha-Synuclein metabolism, tau Proteins genetics, tau Proteins metabolism, Models, Biological, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology
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- 2008
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10. Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration.
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Amador-Ortiz C, Ahmed Z, Zehr C, and Dickson DW
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- Aged, Aged, 80 and over, Cell Death, Dementia metabolism, Female, Glial Fibrillary Acidic Protein metabolism, HLA-DR Antigens metabolism, Hippocampus metabolism, Humans, Male, Middle Aged, Retrospective Studies, Sclerosis metabolism, Synaptophysin metabolism, Ubiquitin metabolism, tau Proteins metabolism, Dementia diagnosis, Hippocampus pathology, Sclerosis classification, Sclerosis diagnosis
- Abstract
Hippocampal sclerosis (HS) is characterized by selective neuronal loss and gliosis in CA1 and the subiculum and has been associated with several disorders, including Alzheimer's disease, frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions (FTLD-U), vascular dementia and some tauopathies. In some cases, HS is not associated with other degenerative pathologies. Such cases are sometimes referred to as HS dementia (HSD). Differences between HSD and HS in the setting of FTLD-U have not been systematically investigated. To this end, eight cases of HSD and ten cases of HS associated with FTLD-U were studied with Nissl and periodic acid-Schiff stains to assess neuronal loss and corpora amylacea, respectively. Sections were immunostained with antibodies to glial fibrillary acidic protein, HLA-DR and synaptophysin and immunoreactivity was measured with image analysis in CA1 and the subiculum of each case. Additionally, sections were immunostained with antibodies to 4-R tau to determine the presence of argyrophilic grains. HSD was different from HS associated with FTLD-U. Specifically, it was more common in the elderly, and it was associated with more marked neuronal and synaptic loss and with greater reactive gliosis. Corpora amylacea tended to be more frequent in HSD than in FTLD-U, but there was no difference in frequency of argyrophilic grains.
- Published
- 2007
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11. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.
- Author
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Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, and Hutton M
- Subjects
- Cell Survival, Codon, Terminator genetics, Dementia physiopathology, Frontal Lobe metabolism, Genetic Linkage genetics, Humans, Intercellular Signaling Peptides and Proteins metabolism, Neurons metabolism, Neurons pathology, Physical Chromosome Mapping, Progranulins, Protein Precursors metabolism, RNA Stability, RNA, Messenger genetics, RNA, Messenger metabolism, Temporal Lobe metabolism, tau Proteins deficiency, tau Proteins genetics, Chromosomes, Human, Pair 17 genetics, Dementia genetics, Frontal Lobe physiopathology, Intercellular Signaling Peptides and Proteins genetics, Mutation genetics, Protein Precursors genetics, Temporal Lobe physiopathology
- Abstract
Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.
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- 2006
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12. Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species.
- Author
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Dickey CA, Yue M, Lin WL, Dickson DW, Dunmore JH, Lee WC, Zehr C, West G, Cao S, Clark AM, Caldwell GA, Caldwell KA, Eckman C, Patterson C, Hutton M, and Petrucelli L
- Subjects
- Animals, Animals, Genetically Modified, Apoptosis, Caenorhabditis elegans genetics, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Caspase 3, Cell Line, Tumor, Enzyme Activation, HSP70 Heat-Shock Proteins genetics, HSP70 Heat-Shock Proteins metabolism, Humans, Mice, Mice, Knockout, Mice, Neurologic Mutants, Molecular Weight, Mutation, Nerve Tissue Proteins metabolism, Neurons metabolism, Phosphorylation, RNA Interference, RNA, Messenger metabolism, Stress, Physiological metabolism, Synapses metabolism, Transcription, Genetic, Ubiquitin-Protein Ligases deficiency, tau Proteins chemistry, tau Proteins genetics, Brain metabolism, Caspases metabolism, Gene Deletion, Ubiquitin-Protein Ligases genetics, tau Proteins metabolism
- Abstract
Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Hereditary mutations in the MAPT gene were shown to promote the formation of structurally distinct tau aggregates in patients that had a parkinsonian-like clinical presentation. Whether tau aggregates themselves or the soluble intermediate species that precede their aggregation are neurotoxic entities in these disorders has yet to be resolved; however, recent in vivo evidence supports the latter. We hypothesized that depletion of CHIP, a tau ubiquitin ligase, would lead to an increase in abnormal tau. Here, we show that deletion of CHIP in mice leads to the accumulation of non-aggregated, ubiquitin-negative, hyperphosphorylated tau species. CHIP-/- mice also have increased neuronal caspase-3 levels and activity, as well as caspase-cleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP-/- mice is insufficient to promote either argyrophilic or "pre-tangle" structures, despite marked phospho-tau accumulation throughout the brain. These observations are supported in post-developmental studies using RNA interference for CHIP (chn-1) in Caenorhabditis elegans and cell culture systems. Our results demonstrate that CHIP is a primary component in the ubiquitin-dependent degradation of tau. We also show that hyperphosphorylation and caspase-3 cleavage of tau both occur before aggregate formation. Based on these findings, we propose that polyubiquitination of tau by CHIP may facilitate the formation of insoluble filamentous tau lesions.
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- 2006
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13. An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice.
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Le Corre S, Klafki HW, Plesnila N, Hübinger G, Obermeier A, Sahagún H, Monse B, Seneci P, Lewis J, Eriksen J, Zehr C, Yue M, McGowan E, Dickson DW, Hutton M, and Roder HM
- Subjects
- Animals, Carbazoles chemistry, Disease Models, Animal, Female, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Structure, Motor Activity physiology, Motor Skills Disorders physiopathology, Okadaic Acid pharmacology, Phosphorylation drug effects, Physical Conditioning, Animal, Rats, Solubility, Transgenes genetics, tau Proteins chemistry, Carbazoles pharmacology, Motor Skills Disorders prevention & control, tau Proteins genetics, tau Proteins metabolism
- Abstract
An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.
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- 2006
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14. Progressive white matter pathology in the spinal cord of transgenic mice expressing mutant (P301L) human tau.
- Author
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Lin WL, Zehr C, Lewis J, Hutton M, Yen SH, and Dickson DW
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- Animals, Axons metabolism, Axons pathology, Axons ultrastructure, Disease Models, Animal, Disease Progression, Genetic Predisposition to Disease genetics, Humans, Macrophages metabolism, Macrophages pathology, Macrophages ultrastructure, Mice, Mice, Transgenic, Microscopy, Electron, Transmission, Mutation genetics, Myelin Sheath metabolism, Myelin Sheath pathology, Myelin Sheath ultrastructure, Myelitis genetics, Myelitis metabolism, Myelitis pathology, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Oligodendroglia metabolism, Oligodendroglia pathology, Oligodendroglia ultrastructure, Spinal Cord metabolism, Spinal Cord pathology, Spinal Cord physiopathology, Spinal Cord Diseases genetics, Spinal Cord Diseases metabolism, Vacuoles metabolism, Vacuoles pathology, Vacuoles ultrastructure, Wallerian Degeneration genetics, Wallerian Degeneration metabolism, tau Proteins genetics, Nerve Fibers, Myelinated metabolism, Nerve Fibers, Myelinated pathology, Neurodegenerative Diseases pathology, Spinal Cord Diseases pathology, Wallerian Degeneration pathology, tau Proteins metabolism
- Abstract
Transgenic mice expressing mutant (P301L) tau develop paresis, neurofibrillary tangles and neuronal loss in spinal motor neurons beginning at 4 to 6 months of age. Astrocytes and oligodendrocytes acquire filamentous tau inclusions at later ages. Here we report pathology in the spinal white matter of these animals. Progressive white matter pathology, detected as early as 2 months of age, was most marked in lateral and anterior columns, with sparing of posterior columns until late in the disease. Early changes in Luxol fast blue/periodic acid Schiff (LFB/PAS) and toluidine blue stained sections were vacuolation of myelin followed by accumulation of myelin figures within previous axonal tubes and finally influx of PAS-positive macrophages. Myelin debris and vacuoles were found in macrophages. At the ultrastructural level, myelinated axons showed extensive vacuolation of myelin sheaths formed by splitting of myelin lamellae at the intra-period line, while axons were atrophic and contained densely packed neurofilaments. Other axons were lost completely, resulting in collapse and phagocytosis of myelin sheaths. Also present were spheroids derived from swollen axons with thin myelin sheaths containing neurofilaments, tau filaments and degenerating organelles. Many oligodendrocytes had membrane-bound cytoplasmic bodies composed of tightly stacked lamellae capped by dense material. The vacuolar myelopathy in this model to some extent resembles that reported in acquired immune deficiency syndrome and vitamin B12 deficiency. The progressive axonal pathology is most consistent with a dying-back process caused by abnormal accumulation of tau in upstream neurons, while vacuolar myelinopathy may be a secondary manifestation of neuroinflammation.
- Published
- 2005
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15. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo.
- Author
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Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, and Duff K
- Subjects
- Animals, Disease Progression, Epitopes, Humans, Image Processing, Computer-Assisted, Immunoblotting, Immunohistochemistry, Immunoprecipitation, Lithium chemistry, Mice, Mice, Transgenic, Neurodegenerative Diseases pathology, Neurons pathology, Phosphorylation, Tauopathies, tau Proteins chemistry, Enzyme Inhibitors pharmacology, Glycogen Synthase Kinase 3 antagonists & inhibitors, Lithium Chloride pharmacology
- Abstract
Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.
- Published
- 2005
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16. Apoptosis in oligodendrocytes is associated with axonal degeneration in P301L tau mice.
- Author
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Zehr C, Lewis J, McGowan E, Crook J, Lin WL, Godwin K, Knight J, Dickson DW, and Hutton M
- Subjects
- Animals, Apoptosis physiology, Brain metabolism, Brain pathology, Caspase 3, Caspases metabolism, Female, Immunohistochemistry, In Situ Nick-End Labeling, Male, Mice, Mice, Transgenic, Microscopy, Electron, Mutation, Neurodegenerative Diseases physiopathology, Neurofilament Proteins metabolism, Oligodendroglia ultrastructure, Spinal Cord metabolism, Spinal Cord pathology, Microtubule-Associated Proteins genetics, Nerve Degeneration pathology, Oligodendroglia pathology, tau Proteins genetics
- Abstract
Transgenic mice overexpressing human tau with the P301L mutation develop neurofibrillary tangles, extensive gliosis, adult-onset motor abnormalities, and neuronal loss in affected brain regions. We investigated the mechanism of neuronal cell death in this model of tauopathy. There was no evidence of neuronal apoptosis at any age; however, a population of oligodendorocytes was immunopositive for TUNEL and activated caspase-3. EM confirmed that these oligodendrocytes were undergoing apoptosis. These data suggest that classical apoptosis is not a major mechanism of neuronal cell death associated with the tau dysfunction in this mouse model; however, prominent white matter pathology in the spinal cord suggests that axonal degeneration in dying neurons causes oligodendrocytes to undergo apoptosis. It is unknown if loss of oligodendrocytes either through apoptosis or through the formation of intracellular tau lesions further contributes to the neurodegeneration seen in these mice.
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- 2004
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17. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease.
- Author
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Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, Olschowka JA, Fonseca MI, O'Banion MK, Tenner AJ, Lemere CA, and Duff K
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- Aging metabolism, Alzheimer Disease genetics, Alzheimer Disease pathology, Alzheimer Disease physiopathology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloidosis genetics, Amyloidosis pathology, Amyloidosis physiopathology, Animals, Complement C1q metabolism, Cyclooxygenase 2, Isoenzymes metabolism, Membrane Proteins genetics, Mice, Mice, Transgenic genetics, Neuroglia physiology, Presenilin-1, Presenilin-2, Prostaglandin-Endoperoxide Synthases metabolism, Tissue Distribution, Alzheimer Disease metabolism, Amyloidosis metabolism, Inflammation Mediators metabolism
- Abstract
Mutations in the amyloid precursor protein (APP) and presenilin-1 and -2 genes (PS-1, -2) cause Alzheimer's disease (AD). Mice carrying both mutant genes (PS/APP) develop AD-like deposits composed of beta-amyloid (Abeta) at an early age. In this study, we have examined how Abeta deposition is associated with immune responses. Both fibrillar and nonfibrillar Abeta (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar Abeta deposits increased up to the oldest age studied (2.5 years old), whereas there were less marked changes in the number of diffuse deposits in mice over 1 year old. Activated microglia and astrocytes increased synchronously with amyloid burden and were, in general, closely associated with deposits. Cyclooxygenase-2, an inflammatory response molecule involved in the prostaglandin pathway, was up-regulated in astrocytes associated with some fibrillar deposits. Complement component 1q, an immune response component, strongly colocalized with fibrillar Abeta, but was also up-regulated in some plaque-associated microglia. These results show: i) an increasing proportion of amyloid is composed of fibrillar Abeta in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse Abeta; and iii) cyclooxygenase-2 and complement component 1q levels increase in response to the formation of fibrillar Abeta in PS/APP mice.
- Published
- 2001
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18. Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion.
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De Jonghe C, Zehr C, Yager D, Prada CM, Younkin S, Hendriks L, Van Broeckhoven C, and Eckman CB
- Subjects
- Amino Acid Sequence, Amyloid beta-Protein Precursor metabolism, Animals, CHO Cells cytology, CHO Cells metabolism, Cell Line, Cricetinae, DNA, Complementary genetics, Humans, Molecular Sequence Data, Mutation, Peptide Fragments metabolism, Plasmids genetics, Recombinant Fusion Proteins genetics, Transfection, Tumor Cells, Cultured cytology, Tumor Cells, Cultured metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics
- Abstract
Mutations in the amyloid beta precursor protein (APP) gene cosegregate with autosomal dominant Alzheimer disease (AD). Brain pathology of AD is characterized by amyloid deposition in senile plaques and by neurofibrillary tangles. Amyloid deposits in AD brains consist of amyloid beta (A beta), a 4-kDa proteolytic product of APP. In contrast, two other mutations in APP, the Flemish APP692 and Dutch APP693 mutations, are associated with autosomal dominant cerebral hemorrhages due to congophilic amyloid angiopathy (CAA) in the presence or absence of AD pathology, respectively. Both mutations are located within A beta near the constitutive cleavage site. While a common effect of AD-linked mutations is to elevate A beta 42 extracellular concentrations, not much is known about the effect of APP692 and APP693. Here we provide evidence that APP692 and APP693 have a different effect on A beta secretion as determined by cDNA transfection experiments. While APP692 upregulates both A beta 40 and A beta 42 secretion, APP693 does not. These data corroborate with previous findings that increased A beta secretion and particularly of A beta 42, is specific for AD pathology.
- Published
- 1998
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19. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.
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Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O'Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, and Duff K
- Subjects
- Alzheimer Disease pathology, Amyloid beta-Protein Precursor biosynthesis, Analysis of Variance, Animals, Brain pathology, Cerebral Cortex pathology, Crosses, Genetic, Genotype, Glial Fibrillary Acidic Protein analysis, Humans, Membrane Proteins biosynthesis, Mice, Mice, Transgenic, Motor Activity, Posture, Presenilin-1, Psychomotor Performance, Reflex, Seizures, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Amyloid beta-Protein Precursor genetics, Membrane Proteins genetics
- Abstract
Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.
- Published
- 1998
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20. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.
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Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, and Younkin S
- Subjects
- Animals, Humans, Membrane Proteins biosynthesis, Mice, Mice, Transgenic, Mutagenesis, Presenilin-1, Amyloid beta-Peptides metabolism, Brain metabolism, Membrane Proteins genetics, Peptide Fragments metabolism
- Abstract
Mutations in the genes encoding amyloid-beta precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early-onset, autosomal dominant Alzheimer's disease. Studies of plasma and fibroblasts from subjects with these mutations have established that they all alter amyloid beta-protein (beta APP) processing, which normally leads to the secretion of amyloid-beta protein (relative molecular mass 4,000; M(r) 4K; approximately 90% A beta1-40, approximately 10% A beta1-42(43)), so that the extracellular concentration of A beta42(43) is increased. This increase in A beta42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because A beta42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of A beta42(43) in the brain and to test whether presenilin mutations act as true (gain of function) dominants, we have now constructed mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, PS1 selectively increases brain A beta42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of A beta42(43) in the brain.
- Published
- 1996
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21. A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease.
- Author
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Perez-Tur J, Croxton R, Wright K, Phillips H, Zehr C, Crook R, Hutton M, Hardy J, Karran E, Roberts GW, Lancaster S, and Haltia T
- Subjects
- Amino Acid Sequence, Humans, Middle Aged, Molecular Sequence Data, Presenilin-1, Alzheimer Disease genetics, Exons, Membrane Proteins genetics, Mutation
- Abstract
Recent studies suggest that mutations in the presenilin 1 gene, which encodes a polypeptide predicted to be a multispanning membrane protein, are responsible for the majority of cases of early onset, autosomal dominant Alzheimer's disease. Here we describe a further mutation in the presenilin 1 gene (R269G) in a family with early onset Alzheimer's disease. This mutation is in exon 8 which appears to be a favoured region for pathogenic mutations. In the presenilin protein the region coded for by this exon is likely to comprise a domain located on the membrane surface. We discuss the likely effects of the exon 8 mutations on the structure of the exon and in the pathogenesis of the disease.
- Published
- 1996
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