53 results on '"Albers MW"'
Search Results
2. Determinants of Persistence and Recovery of Chronic COVID19 Chemosensory Dysfunction.
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Minichetti DG, Boyd A, Lemire E, Hacker J, Haber AL, Roditi RE, Albers MW, Lee S, Buchheit KM, Laidlaw TM, and Bankova LG
- Abstract
Background: In 2-4% of patients, COVID19 chemosensory dysfunction (CSD) persists beyond six months, accounting for up to 4 million people in the US. The predictors of persistence and recovery require further exploration., Objective: To define the predictors of recovery and assess the quality of CSD in registry subjects with self-reported persistent smell and taste dysfunction after COVID19., Methods: COVID19 CSD participants (n=408) from the four major waves of the pandemic completed questionnaires at four time points between 2021 and 2023, assessing demographics, sinonasal symptoms and self-assessed recovery. Objective measurements of smell (UPSIT) and taste (BWETT) were performed on a sub-cohort (n=108)., Results: In this chronic CSD cohort, the average symptom duration was 24±5 months but 70% those who contracted COVID19 in 2020 have ongoing dysfunction. Phantosmia and dysgeusia were most prevalent in the early waves of COVID19, while most participants reported disrupted ability to distinguish scents and flavors and undulating chemosensory function. Subjects reported low incidence of subjective sinonasal symptoms but high prevalence of sleep and mood disturbance. Cigarette phantom smells were predictive of persistence of CSD. Conversely, self-reported environmental allergies were predictive of recovery and dust mite allergies, specifically, were negative predictors of cigarette phantom smells. Finally, no treatment resolved CSD, but nasal steroids were reported effective by recovered CSD subjects. Objective measures of both smell and taste were significantly reduced in chronic CSD compared to controls., Conclusions: Chronic COVID19 CSD is a syndrome resistant to standard anti-inflammatory therapy. Pre-existing environmental allergies and hypertension predict recovery, while cigarette smoke phantosmia predicts persistence., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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3. AROMHA Brain Health Test: A Remote Olfactory Assessment as a Screen for Cognitive Impairment.
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Jobin B, Magdamo C, Delphus D, Runde A, Reineke S, Soto AA, Ergun B, Albers AD, and Albers MW
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Cost-effective, noninvasive screening methods for preclinical Alzheimer's disease (AD) and other neurocognitive disorders remain an unmet need. The olfactory neural circuits develop AD pathological changes prior to symptom onset. To probe these vulnerable circuits, we developed the digital remote AROMHA Brain Health Test (ABHT), an at-home odor identification, discrimination, memory, and intensity assessment. The ABHT was self-administered among cognitively normal (CN) English and Spanish speakers (n=127), participants with subjective cognitive complaints (SCC; n=34), and mild cognitive impairment (MCI; n=19). Self-administered tests took place remotely at home under unobserved (among interested CN participants) and observed modalities (CN, SCC, and MCI), as well as in-person with a research assistant present (CN, SCC, and MCI). Olfactory performance was similar across observed and unobserved remote self-administration and between English and Spanish speakers. Odor memory, identification, and discrimination scores decreased with age, and olfactory identification and discrimination were lower in the MCI group compared to CN and SCC groups, independent of age, sex, and education. The ABHT revealed age-related olfactory decline, and discriminated CN older adults from those with cognitive impairment. Replication of our results in other populations would support the use of the ABHT to identify and monitor individuals at risk for developing dementia.
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- 2024
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4. TYK2 as a novel therapeutic target in Alzheimer's Disease with TDP-43 inclusions.
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König LE, Rodriguez S, Hug C, Daneshvari S, Chung A, Bradshaw GA, Sahin A, Zhou G, Eisert RJ, Piccioni F, Das S, Kalocsay M, Sokolov A, Sorger P, Root DE, and Albers MW
- Abstract
Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)
1,2 and amyotrophic lateral sclerosis (ALS)3 , raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS4 . CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death4 . Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases., Competing Interests: COMPETING INTERESTS M.W.A. is a consultant for TLL, LLC, Transposon Therapeutics, and has received in kind support from Eli Lilly that is not related to this work. A.S. is an employee at Flagship Labs 84, Inc., a subsidiary of Flagship Pioneering. F.P. is an employee of Merck Research Laboratories.- Published
- 2024
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5. Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging.
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Diez I, Ortiz-Terán L, Ng TSC, Albers MW, Marshall G, Orwig W, Kim CM, Bueichekú E, Montal V, Olofsson J, Vannini P, El Fahkri G, Sperling R, Johnson K, Jacobs HIL, and Sepulcre J
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- Humans, Female, Male, Aged, Aged, 80 and over, Olfactory Pathways metabolism, Olfactory Pathways diagnostic imaging, Smell physiology, Brain metabolism, Brain diagnostic imaging, Temporal Lobe metabolism, Temporal Lobe diagnostic imaging, Middle Aged, tau Proteins metabolism, tau Proteins genetics, Olfactory Perception physiology, Aging physiology, Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease diagnostic imaging, Alzheimer Disease physiopathology, Positron-Emission Tomography
- Abstract
The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system., (© 2024. The Author(s).)
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- 2024
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6. Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations.
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Verma AK, Lowery S, Lin LC, Duraisami E, Lloréns JEA, Qiu Q, Hefti M, Yu CR, Albers MW, and Perlman S
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Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation., Competing Interests: Conflict of Interest The authors declare no conflict of interest directly related to this study. MWA is a cofounder and owns shares in Aromha, Inc. He has received in kind contributions from Eli Lilly and research support from TLL Pharma. He is an SAB member of Sudo Therapeutics, and consults for BMS and Transposon.
- Published
- 2024
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7. Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.
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Marques C, Held A, Dorfman K, Sung J, Song C, Kavuturu AS, Aguilar C, Russo T, Oakley DH, Albers MW, Hyman BT, Petrucelli L, Lagier-Tourenne C, and Wainger BJ
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- Animals, Humans, Mice, C9orf72 Protein genetics, Motor Neurons metabolism, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Induced Pluripotent Stem Cells metabolism, Pick Disease of the Brain
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The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD., (© 2024. The Author(s).)
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- 2024
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8. causalCmprsk: An R package for nonparametric and Cox-based estimation of average treatment effects in competing risks data.
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Vakulenko-Lagun B, Magdamo C, Charpignon ML, Zheng B, Albers MW, and Das S
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- Humans, Hospital Mortality, Proportional Hazards Models, Survival Analysis, Probability, Models, Statistical
- Abstract
Background and Objective: Competing risks data arise in both observational and experimental clinical studies with time-to-event outcomes, when each patient might follow one of the multiple mutually exclusive competing paths. Ignoring competing risks in the analysis can result in biased conclusions. In addition, possible confounding bias of the treatment-outcome relationship has to be addressed, when estimating treatment effects from observational data. In order to provide tools for estimation of average treatment effects on time-to-event outcomes in the presence of competing risks, we developed the R package causalCmprsk. We illustrate the package functionality in the estimation of effects of a right heart catheterization procedure on discharge and in-hospital death from observational data., Methods: The causalCmprsk package implements an inverse probability weighting estimation approach, aiming to emulate baseline randomization and alleviate possible treatment selection bias. The package allows for different types of weights, representing different target populations. causalCmprsk builds on existing methods from survival analysis and adapts them to the causal analysis in non-parametric and semi-parametric frameworks., Results: The causalCmprsk package has two main functions: fit.cox assumes a semiparametric structural Cox proportional hazards model for the counterfactual cause-specific hazards, while fit.nonpar does not impose any structural assumptions. In both frameworks, causalCmprsk implements estimators of (i) absolute risks for each treatment arm, e.g., cumulative hazards or cumulative incidence functions, and (ii) relative treatment effects, e.g., hazard ratios, or restricted mean time differences. The latter treatment effect measure translates the treatment effect from probability into more intuitive time domain and allows the user to quantify, for example, by how many days or months the treatment accelerates the recovery or postpones illness or death., Conclusions: The causalCmprsk package provides a convenient and useful tool for causal analysis of competing risks data. It allows the user to distinguish between different causes of the end of follow-up and provides several time-varying measures of treatment effects. The package is accompanied by a vignette that contains more details, examples and code, making the package accessible even for non-expert users., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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9. Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia.
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Charpignon ML, Vakulenko-Lagun B, Zheng B, Magdamo C, Su B, Evans K, Rodriguez S, Sokolov A, Boswell S, Sheu YH, Somai M, Middleton L, Hyman BT, Betensky RA, Finkelstein SN, Welsch RE, Tzoulaki I, Blacker D, Das S, and Albers MW
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- Humans, Drug Repositioning, Network Pharmacology, Sulfonylurea Compounds, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Medical Records, Metformin pharmacology, Metformin therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 complications, Dementia drug therapy, Dementia etiology
- Abstract
Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain., (© 2022. The Author(s).)
- Published
- 2022
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10. International consensus statement on allergy and rhinology: Olfaction.
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Patel ZM, Holbrook EH, Turner JH, Adappa ND, Albers MW, Altundag A, Appenzeller S, Costanzo RM, Croy I, Davis GE, Dehgani-Mobaraki P, Doty RL, Duffy VB, Goldstein BJ, Gudis DA, Haehner A, Higgins TS, Hopkins C, Huart C, Hummel T, Jitaroon K, Kern RC, Khanwalkar AR, Kobayashi M, Kondo K, Lane AP, Lechner M, Leopold DA, Levy JM, Marmura MJ, Mclelland L, Miwa T, Moberg PJ, Mueller CA, Nigwekar SU, O'Brien EK, Paunescu TG, Pellegrino R, Philpott C, Pinto JM, Reiter ER, Roalf DR, Rowan NR, Schlosser RJ, Schwob J, Seiden AM, Smith TL, Soler ZM, Sowerby L, Tan BK, Thamboo A, Wrobel B, and Yan CH
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- Consensus, Cost of Illness, Humans, Hypersensitivity, Smell
- Abstract
Background: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O)., Methods: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus., Results: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies., Conclusion: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further., (© 2022 ARS-AAOA, LLC.)
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- 2022
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11. Olfactory Function and Markers of Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimer's Disease.
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Ramirez-Gomez L, Albers MW, Baena A, Vila-Castelar C, Fox-Fuller JT, Sanchez J, Jain F, Albers AD, Lopera F, and Quiroz YT
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- Amyloid beta-Peptides metabolism, Biomarkers, Brain pathology, Cross-Sectional Studies, Humans, Magnetic Resonance Imaging methods, Positron-Emission Tomography methods, tau Proteins genetics, tau Proteins metabolism, Alzheimer Disease diagnostic imaging, Alzheimer Disease genetics, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction genetics, Cognitive Dysfunction pathology, Olfaction Disorders etiology, Olfaction Disorders genetics
- Abstract
Background: Olfactory dysfunction is one of the earliest signs of Alzheimer's disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia., Objective: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members., Methods: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging., Results: Worse olfactory identification performance was associated with greater age in mutation carriers (r = -0.52 p = 0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r = 0.55, p = 0.024) and CERAD delayed recall (r = 0.63, p = 0.007) and greater cortical amyloid-β (r = -0.53, p = 0.042) and tau pathology burden (entorhinal: r = -0.59, p = 0.016; inferior temporal: r = -0.52, p = 0.038)., Conclusion: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.
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- 2022
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12. Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer's disease.
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Madrasi K, Das R, Mohmmadabdul H, Lin L, Hyman BT, Lauffenburger DA, Albers MW, Rissman RA, Burke JM, Apgar JF, Wille L, Gruenbaum L, and Hua F
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- Amyloid Precursor Protein Secretases therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Humans, Alzheimer Disease drug therapy, Alzheimer Disease immunology, Amyloid beta-Peptides drug effects, Amyloid beta-Peptides metabolism, Computer Simulation, Network Pharmacology, Pharmaceutical Preparations
- Abstract
Introduction: Despite strong evidence linking amyloid beta (Aβ) to Alzheimer's disease, most clinical trials have shown no clinical efficacy for reasons that remain unclear. To understand why, we developed a quantitative systems pharmacology (QSP) model for seven therapeutics: aducanumab, crenezumab, solanezumab, bapineuzumab, elenbecestat, verubecestat, and semagacestat., Methods: Ordinary differential equations were used to model the production, transport, and aggregation of Aβ; pharmacology of the drugs; and their impact on plaque., Results: The calibrated model predicts that endogenous plaque turnover is slow, with an estimated half-life of 2.75 years. This is likely why beta-secretase inhibitors have a smaller effect on plaque reduction. Of the mechanisms tested, the model predicts binding to plaque and inducing antibody-dependent cellular phagocytosis is the best approach for plaque reduction., Discussion: A QSP model can provide novel insights to clinical results. Our model explains the results of clinical trials and provides guidance for future therapeutic development., (© 2021 Applied BioMath. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
- Published
- 2021
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13. Post-viral effects of COVID-19 in the olfactory system and their implications.
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Xydakis MS, Albers MW, Holbrook EH, Lyon DM, Shih RY, Frasnelli JA, Pagenstecher A, Kupke A, Enquist LW, and Perlman S
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- Brain diagnostic imaging, Brain physiopathology, Brain virology, COVID-19 physiopathology, Humans, Neurodegenerative Diseases diagnostic imaging, Neurodegenerative Diseases etiology, Neurodegenerative Diseases physiopathology, Olfaction Disorders physiopathology, Olfaction Disorders virology, Olfactory Mucosa physiopathology, Olfactory Mucosa virology, Prospective Studies, Smell physiology, COVID-19 complications, COVID-19 diagnostic imaging, Olfaction Disorders diagnostic imaging, Olfaction Disorders etiology, Olfactory Mucosa diagnostic imaging
- Abstract
Background: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge., Recent Developments: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease., Competing Interests: Declaration of interests SP reports grants from the US National Institutes of Health. AP reports grants from the German Ministry of Education and Research. MWA reports non-financial support from International Flavor & Fragrances, funding from the US National Institutes of Health Rapid Acceleration of Diagnostics (RADx), and a pending COVID-19 smell test patent. All other authors declare no competing interests. The views expressed in this manuscript do not necessarily reflect the official position of the US Department of Defense., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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14. Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss.
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Rodriguez S, Sahin A, Schrank BR, Al-Lawati H, Costantino I, Benz E, Fard D, Albers AD, Cao L, Gomez AC, Evans K, Ratti E, Cudkowicz M, Frosch MP, Talkowski M, Sorger PK, Hyman BT, and Albers MW
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- Animals, Brain metabolism, DNA Repeat Expansion, Humans, Mice, RNA, Double-Stranded, Amyotrophic Lateral Sclerosis genetics, C9orf72 Protein genetics, Frontotemporal Dementia genetics
- Abstract
Triggers of innate immune signaling in the CNS of patients with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G
4 C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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15. Machine learning identifies candidates for drug repurposing in Alzheimer's disease.
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Rodriguez S, Hug C, Todorov P, Moret N, Boswell SA, Evans K, Zhou G, Johnson NT, Hyman BT, Sorger PK, Albers MW, and Sokolov A
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- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Cerebral Cortex pathology, Drug Repositioning, Drugs, Investigational chemistry, Gene Expression Profiling, Gene Expression Regulation, High-Throughput Screening Assays, Humans, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins metabolism, Neurons drug effects, Neurons metabolism, Neurons pathology, Neuroprotective Agents chemistry, Nootropic Agents chemistry, Pharmacogenetics methods, Pharmacogenetics statistics & numerical data, Polypharmacology, Prescription Drugs chemistry, Primary Cell Culture, Severity of Illness Index, Alzheimer Disease drug therapy, Drugs, Investigational pharmacology, Machine Learning, Nerve Tissue Proteins genetics, Neuroprotective Agents pharmacology, Nootropic Agents pharmacology, Prescription Drugs pharmacology
- Abstract
Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.
- Published
- 2021
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16. COVID-19 and the Chemical Senses: Supporting Players Take Center Stage.
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Cooper KW, Brann DH, Farruggia MC, Bhutani S, Pellegrino R, Tsukahara T, Weinreb C, Joseph PV, Larson ED, Parma V, Albers MW, Barlow LA, Datta SR, and Di Pizio A
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- Animals, COVID-19, Coronavirus Infections epidemiology, Humans, Olfaction Disorders epidemiology, Olfaction Disorders virology, Olfactory Bulb physiopathology, Olfactory Bulb virology, Olfactory Mucosa physiopathology, Olfactory Mucosa virology, Pandemics, Pneumonia, Viral epidemiology, SARS-CoV-2, Taste Disorders epidemiology, Taste Disorders virology, Betacoronavirus, Coronavirus Infections physiopathology, Olfaction Disorders physiopathology, Pneumonia, Viral physiopathology, Smell physiology, Taste physiology, Taste Disorders physiopathology
- Abstract
The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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17. Innate immune signaling in the olfactory epithelium reduces odorant receptor levels: modeling transient smell loss in COVID-19 patients.
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Rodriguez S, Cao L, Rickenbacher GT, Benz EG, Magdamo C, Gomez LR, Holbrook EH, Albers AD, Gallagher R, Westover MB, Evans KE, Tatar DJ, Mukerji S, Zafonte R, Boyer EW, Yu CR, and Albers MW
- Abstract
Post-infectious anosmias typically follow death of olfactory sensory neurons (OSNs) with a months-long recovery phase associated with parosmias. While profound anosmia is the leading symptom associated with COVID-19 infection, many patients regain olfactory function within days to weeks without distortions. Here, we demonstrate that sterile induction of anti-viral type I interferon signaling in the mouse olfactory epithelium is associated with diminished odor discrimination and reduced odor-evoked local field potentials. RNA levels of all class I, class II, and TAAR odorant receptors are markedly reduced in OSNs in a non-cell autonomous manner. We find that people infected with COVID-19 rate odors with lower intensities and have odor discrimination deficits relative to people that tested negative for COVID-19. Taken together, we propose that inflammatory-mediated loss of odorant receptor expression with preserved circuit integrity accounts for the profound anosmia and rapid recovery of olfactory function without parosmias caused by COVID-19.
- Published
- 2020
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18. Loss of Ataxin-1 Potentiates Alzheimer's Pathogenesis by Elevating Cerebral BACE1 Transcription.
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Suh J, Romano DM, Nitschke L, Herrick SP, DiMarzio BA, Dzhala V, Bae JS, Oram MK, Zheng Y, Hooli B, Mullin K, Gennarino VA, Wasco W, Schmahmann JD, Albers MW, Zoghbi HY, and Tanzi RE
- Subjects
- Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases genetics, Amyloid beta-Protein Precursor metabolism, Animals, Ataxin-1 deficiency, Ataxin-1 genetics, Brain pathology, CA2 Region, Hippocampal metabolism, CA2 Region, Hippocampal pathology, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Disease Models, Animal, Female, Gene Frequency, Humans, Male, Mice, Mice, Transgenic, Neurogenesis, Proto-Oncogene Proteins c-ets genetics, Proto-Oncogene Proteins c-ets metabolism, Transcription Factors genetics, Transcription Factors metabolism, Transcription, Genetic, Trinucleotide Repeats genetics, Up-Regulation, Alzheimer Disease pathology, Amyloid Precursor Protein Secretases metabolism, Ataxin-1 metabolism, Brain metabolism
- Abstract
Expansion of CAG trinucleotide repeats in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordination and cognition. While ATXN1 is associated with increased Alzheimer's disease (AD) risk, CAG repeat number in AD patients is not changed. Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout of Atxn1 reduced CIC-ETV4/5-mediated inhibition of Bace1 transcription, leading to increased BACE1 levels and enhanced amyloidogenic cleavage of APP, selectively in AD-vulnerable brain regions. Elevated BACE1 expression exacerbated Aβ deposition and gliosis in AD mouse models and impaired hippocampal neurogenesis and olfactory axonal targeting. In SCA1 mice, polyglutamine-expanded mutant ataxin-1 led to the increase of BACE1 post-transcriptionally, both in cerebrum and cerebellum, and caused axonal-targeting deficit and neurodegeneration in the hippocampal CA2 region. These findings suggest that loss of ataxin-1 elevates BACE1 expression and Aβ pathology, rendering it a potential contributor to AD risk and pathogenesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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19. A dynamic view of the proteomic landscape during differentiation of ReNcell VM cells, an immortalized human neural progenitor line.
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Song Y, Subramanian K, Berberich MJ, Rodriguez S, Latorre IJ, Luria CM, Everley R, Albers MW, Mitchison TJ, and Sorger PK
- Subjects
- Cell Line, Cell Movement, Humans, Neurons cytology, Tandem Mass Spectrometry, Neural Stem Cells cytology, Neural Stem Cells metabolism, Neurogenesis physiology, Proteome analysis
- Abstract
The immortalized human ReNcell VM cell line represents a reproducible and easy-to-propagate cell culture system for studying the differentiation of neural progenitors. To better characterize the starting line and its subsequent differentiation, we assessed protein and phospho-protein levels and cell morphology over a 15-day period during which ReNcell progenitors differentiated into neurons, astrocytes and oligodendrocytes. Five of the resulting datasets measured protein levels or states of phosphorylation based on tandem-mass-tag (TMT) mass spectrometry and four datasets characterized cellular phenotypes using high-content microscopy. Proteomic analysis revealed reproducible changes in pathways responsible for cytoskeletal rearrangement, cell phase transitions, neuronal migration, glial differentiation, neurotrophic signalling and extracellular matrix regulation. Proteomic and imaging data revealed accelerated differentiation in cells treated with the poly-selective CDK and GSK3 inhibitor kenpaullone or the HMG-CoA reductase inhibitor mevastatin, both of which have previously been reported to promote neural differentiation. These data provide in-depth information on the ReNcell progenitor state and on neural differentiation in the presence and absence of drugs, setting the stage for functional studies.
- Published
- 2019
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20. Olanzapine Improved Symptoms and Olfactory Function in an Olfactory Reference Syndrome Patient.
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Albers AD, Amato I, and Albers MW
- Subjects
- Aged, Humans, Male, Neuropsychological Tests, Odorants, Olanzapine therapeutic use, Olfaction Disorders drug therapy
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- 2018
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21. Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in Mouse Models of Down Syndrome.
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William CM, Saqran L, Stern MA, Chiang CL, Herrick SP, Rangwala A, Albers MW, Frosch MP, and Hyman BT
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- Animals, Blindness physiopathology, Cytoskeletal Proteins genetics, Dominance, Ocular, Female, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Nerve Tissue Proteins genetics, Neuronal Plasticity, Visual Cortex physiopathology, Down Syndrome physiopathology, Olfactory Pathways physiopathology, Smell, Vision, Ocular, Visual Pathways physiopathology
- Abstract
Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivo SIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients., (Copyright © 2017 the authors 0270-6474/17/379880-09$15.00/0.)
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- 2017
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22. Nasal neuron PET imaging quantifies neuron generation and degeneration.
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Van de Bittner GC, Riley MM, Cao L, Ehses J, Herrick SP, Ricq EL, Wey HY, O'Neill MJ, Ahmed Z, Murray TK, Smith JE, Wang C, Schroeder FA, Albers MW, and Hooker JM
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- Animals, Male, Olfaction Disorders physiopathology, Olfactory Nerve physiopathology, Olfactory Pathways physiopathology, Radioactive Tracers, Rats, Rats, Sprague-Dawley, Tauopathies physiopathology, Aging, Olfaction Disorders diagnostic imaging, Olfactory Nerve diagnostic imaging, Olfactory Pathways diagnostic imaging, Positron-Emission Tomography methods, Tauopathies diagnostic imaging
- Abstract
Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics., Competing Interests: G.C. Van de Bittner and J.M. Hooker are inventors on a patent application related to this work (Radiolabeled compounds for imaging – PCT/US2015/040971). M.J. O’Neill, Z. Ahmed, and T.K. Murray receive a salary for their work at Eli Lilly and Co. Ltd.
- Published
- 2017
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23. Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly.
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Dhilla Albers A, Asafu-Adjei J, Delaney MK, Kelly KE, Gomez-Isla T, Blacker D, Johnson KA, Sperling RA, Hyman BT, Betensky RA, Hastings L, and Albers MW
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- Aged, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease pathology, Atrophy pathology, Biomarkers, Case-Control Studies, Cognitive Dysfunction genetics, Cognitive Dysfunction pathology, Cross-Sectional Studies, Entorhinal Cortex pathology, Female, Hippocampus pathology, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Positron Emission Tomography Computed Tomography, Alzheimer Disease psychology, Apolipoprotein E4 genetics, Cognitive Dysfunction psychology, Memory, Episodic, Neuropsychological Tests, Olfactory Perception, Plaque, Amyloid pathology
- Abstract
Objective: The objective of this study was to relate a novel test of identifying and recalling odor percepts to biomarkers of Alzheimer's disease (AD) in well-characterized elderly individuals, ranging from cognitively normal to demented., Methods: One hundred eighty-three participants (cognitively normal: n = 70; subjective cognitive concerns: n = 74; mild cognitive impairment [MCI]: n = 29, AD dementia: n = 10) were administered novel olfactory tests: the Odor Percept IDentification (OPID) and the Percepts of Odor Episodic Memory (POEM) tests. Univariate cross-sectional analyses of performance across diagnoses; logistic regression modeling, including covariates of age, sex, education, APOE genotype, and neuropsychological test scores; and linear mixed modeling of longitudinal cognitive scores were performed. Amyloid deposition and MRI volumetrics were analyzed in a subset of participants., Results: Accuracy of identification and episodic memory of odor percepts differed significantly across diagnosis and age, with progressively worse performance across degrees of impairment. Among the participants who were cognitively normal or had subjective cognitive concerns, poorer than expected performance on the POEM test (based on the same individual's performance on the OPID and odor discrimination tests) was associated with higher frequencies of the APOE ε4 allele, thinner entorhinal cortices, and worse longitudinal trajectory of Logical Memory scores., Interpretation: Selective impairment of episodic memory of odor percepts, relative to identification and discrimination of odor percepts revealed by this novel POEM battery, is associated with biomarkers of AD in a well-characterized pre-MCI population. These affordable, noninvasive olfactory tests offer potential to identify clinically normal individuals who have greater likelihood of future cognitive decline. Ann Neurol 2016;80:846-857., Competing Interests: Potential Conflicts of Interest: Dr. Hastings is the founder, owns stock, and receives a salary for serving as President of Osmic Enterprises, Inc., which markets the OPID and POEM tests. Dr. M. Albers receives consulting fees from International Flavors and Fragrances. All other authors do not have relationships with commercial enterprises that are of direct relevance to the current research., (© 2016 American Neurological Association.)
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- 2016
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24. Massachusetts Alzheimer's Disease Research Center: progress and challenges.
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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
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25. Odor identification and Alzheimer disease biomarkers in clinically normal elderly.
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Growdon ME, Schultz AP, Dagley AS, Amariglio RE, Hedden T, Rentz DM, Johnson KA, Sperling RA, Albers MW, and Marshall GA
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- Aged, Aged, 80 and over, Amyloid beta-Peptides metabolism, Biomarkers, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Memory, Episodic, Positron-Emission Tomography, Aging metabolism, Aging pathology, Aging physiology, Alzheimer Disease diagnosis, Entorhinal Cortex metabolism, Entorhinal Cortex pathology, Entorhinal Cortex physiopathology, Hippocampus metabolism, Hippocampus pathology, Hippocampus physiopathology, Olfaction Disorders metabolism, Olfaction Disorders pathology, Olfaction Disorders physiopathology
- Abstract
Objectives: Our objective was to investigate cross-sectional associations between odor identification ability and imaging biomarkers of neurodegeneration and amyloid deposition in clinically normal (CN) elderly individuals, specifically testing the hypothesis that there may be an interaction between amyloid deposition and neurodegeneration in predicting odor identification dysfunction., Methods: Data were collected on 215 CN participants from the Harvard Aging Brain Study. Measurements included the 40-item University of Pennsylvania Smell Identification Test and neuropsychological testing, hippocampal volume (HV) and entorhinal cortex (EC) thickness from MRI, and amyloid burden using Pittsburgh compound B (PiB) PET. A linear regression model with backward elimination (p < 0.05 retention) evaluated the cross-sectional association between the University of Pennsylvania Smell Identification Test and amyloid burden, HV, and EC thickness, assessing for effect modification by PiB status. Covariates included age, sex, premorbid intelligence, APOE ε4 carrier status, and Boston Naming Test., Results: In unadjusted univariate analyses, worse olfaction was associated with decreased HV (p < 0.001), thinner EC (p = 0.003), worse episodic memory (p = 0.03), and marginally associated with greater amyloid burden (binary PiB status, p = 0.06). In the multivariate model, thinner EC in PiB-positive individuals (interaction term) was associated with worse olfaction (p = 0.02)., Conclusions: In CN elderly, worse odor identification was associated with markers of neurodegeneration. Furthermore, individuals with elevated cortical amyloid and thinner EC exhibited worse odor identification, elucidating the potential contribution of olfactory testing to detect preclinical AD in CN individuals., (© 2015 American Academy of Neurology.)
- Published
- 2015
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26. At the interface of sensory and motor dysfunctions and Alzheimer's disease.
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Albers MW, Gilmore GC, Kaye J, Murphy C, Wingfield A, Bennett DA, Boxer AL, Buchman AS, Cruickshanks KJ, Devanand DP, Duffy CJ, Gall CM, Gates GA, Granholm AC, Hensch T, Holtzer R, Hyman BT, Lin FR, McKee AC, Morris JC, Petersen RC, Silbert LC, Struble RG, Trojanowski JQ, Verghese J, Wilson DA, Xu S, and Zhang LI
- Subjects
- Alzheimer Disease diagnosis, Disease Progression, Early Diagnosis, Humans, Movement Disorders diagnosis, National Institute on Aging (U.S.), Sensation Disorders diagnosis, United States, Aging physiology, Alzheimer Disease physiopathology, Movement Disorders physiopathology, Sensation Disorders physiopathology
- Abstract
Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled "Sensory and Motor Dysfunctions in Aging and AD." The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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27. Tau-amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid-induced disruption of axonal projections and exacerbated axonal pathology.
- Author
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Pooler AM, Polydoro M, Wegmann SK, Pitstick R, Kay KR, Sanchez L, Carlson GA, Gomez-Isla T, Albers MW, Spires-Jones TL, and Hyman BT
- Subjects
- Alzheimer Disease metabolism, Animals, Axons metabolism, Disease Models, Animal, Humans, Immunohistochemistry, Mice, Mice, Transgenic, Neural Pathways metabolism, Neurofibrillary Tangles metabolism, Neurofibrillary Tangles pathology, Plaque, Amyloid metabolism, Tissue Array Analysis, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Axons pathology, Neural Pathways pathology, tau Proteins metabolism
- Abstract
Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimer's disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle-bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimer's disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex) and mutant APP/PS1 (in a widespread distribution) to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau-expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau-containing axons. Moreover, human P301L tau-containing axons appear to increase the extent of dystrophic axons around plaques. Thus, the presence of amyloid deposits in the axonal terminal zone of pathological tau-containing neurons profoundly impacts their normal connectivity., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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28. Synaptic plasticity defect following visual deprivation in Alzheimer's disease model transgenic mice.
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William CM, Andermann ML, Goldey GJ, Roumis DK, Reid RC, Shatz CJ, Albers MW, Frosch MP, and Hyman BT
- Subjects
- Alzheimer Disease genetics, Amyloid beta-Protein Precursor genetics, Animals, Eye Enucleation, Fluorescence, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons physiology, Photic Stimulation, Polymerase Chain Reaction, Presenilin-1 genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, Visual Cortex cytology, Visual Cortex physiology, Alzheimer Disease physiopathology, Neuronal Plasticity physiology, Sensory Deprivation physiology, Synapses physiology, Vision, Ocular physiology
- Abstract
Amyloid-β (Aβ)-induced changes in synaptic function in experimental models of Alzheimer's disease (AD) suggest that Aβ generation and accumulation may affect fundamental mechanisms of synaptic plasticity. To test this hypothesis, we examined the effect of APP overexpression on a well characterized, in vivo, developmental model of systems-level plasticity, ocular dominance plasticity. Following monocular visual deprivation during the critical period, mice that express mutant alleles of amyloid precursor protein (APPswe) and Presenilin1 (PS1dE9), as well as mice that express APPswe alone, lack ocular dominance plasticity in visual cortex. Defects in the spatial extent and magnitude of the plastic response are evident using two complementary approaches, Arc induction and optical imaging of intrinsic signals in awake mice. This defect in a classic paradigm of systems level synaptic plasticity shows that Aβ overexpression, even early in postnatal life, can perturb plasticity in cerebral cortex, and supports the idea that decreased synaptic plasticity due to elevated Aβ exposure contributes to cognitive impairment in AD.
- Published
- 2012
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29. The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease.
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Cao L, Rickenbacher GT, Rodriguez S, Moulia TW, and Albers MW
- Subjects
- Amyloid Precursor Protein Secretases genetics, Animals, Aspartic Acid Endopeptidases genetics, Immunohistochemistry, Mice, Mice, Transgenic, Olfactory Bulb enzymology, Sensory Receptor Cells enzymology, Amyloid Precursor Protein Secretases metabolism, Aspartic Acid Endopeptidases metabolism, Axons, Olfactory Bulb metabolism, Sensory Receptor Cells metabolism
- Abstract
The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is necessary to generate the Aβ peptide, which is implicated in Alzheimer's disease pathology. Studies show that the expression of BACE1 and its protease activity are tightly regulated, but the physiological function of BACE1 remains poorly understood. Recently, numerous axon guidance proteins were identified as potential substrates of BACE1. Here, we examined the consequences of loss of BACE1 function in a well-defined in vivo model system of axon guidance, mouse olfactory sensory neurons (OSNs). The BACE1 protein resides predominantly in proximal segment and the termini of OSN axons, and the expression of BACE1 inversely correlates with odor-evoked neural activity. The precision of targeting of OSN axons is disturbed in both BACE1 null and, surprisingly, in BACE1 heterozygous mice. We propose that BACE1 cleavage of axon guidance proteins is essential to maintain the connectivity of OSNs in vivo.
- Published
- 2012
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30. Loss of the V-ATPase B1 subunit isoform expressed in non-neuronal cells of the mouse olfactory epithelium impairs olfactory function.
- Author
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Păunescu TG, Rodriguez S, Benz E, McKee M, Tyszkowski R, Albers MW, and Brown D
- Subjects
- Animals, Cell Membrane metabolism, Immunohistochemistry, Male, Mice, Microscopy, Electron, Microvilli metabolism, Odorants, Olfactory Bulb cytology, Olfactory Mucosa metabolism, Protein Isoforms metabolism, Sensory Receptor Cells metabolism, Vacuolar Proton-Translocating ATPases metabolism
- Abstract
The vacuolar proton-pumping ATPase (V-ATPase) is the main mediator of intracellular organelle acidification and also regulates transmembrane proton (H(+)) secretion, which is necessary for an array of physiological functions fulfilled by organs such as the kidney, male reproductive tract, lung, bone, and ear. In this study we characterize expression of the V-ATPase in the main olfactory epithelium of the mouse, as well as a functional role for the V-ATPase in odor detection. We report that the V-ATPase localizes to the apical membrane microvilli of olfactory sustentacular cells and to the basolateral membrane of microvillar cells. Plasma membrane V-ATPases containing the B1 subunit isoform are not detected in olfactory sensory neurons or in the olfactory bulb. This precise localization of expression affords the opportunity to ascertain the functional relevance of V-ATPase expression upon innate, odor-evoked behaviors in B1-deficient mice. This animal model exhibits diminished innate avoidance behavior (revealed as a decrease in freezing time and an increase in the number of sniffs in the presence of trimethyl-thiazoline) and diminished innate appetitive behavior (a decrease in time spent investigating the urine of the opposite sex). We conclude that V-ATPase-mediated H(+) secretion in the olfactory epithelium is required for optimal olfactory function.
- Published
- 2012
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31. Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo.
- Author
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Cao L, Schrank BR, Rodriguez S, Benz EG, Moulia TW, Rickenbacher GT, Gomez AC, Levites Y, Edwards SR, Golde TE, Hyman BT, Barnea G, and Albers MW
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Animals, Axons metabolism, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Transgenic, Plaque, Amyloid metabolism, Alzheimer Disease metabolism, Alzheimer Disease physiopathology, Amyloid beta-Peptides metabolism, Neural Conduction, Olfactory Perception, Sensory Receptor Cells physiology
- Abstract
The amyloid beta peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) before the onset of plaques. Expression of human APPsw exclusively in olfactory sensory neurons also perturbs connectivity with associated reductions in odour-evoked gene expression and olfactory acuity. By contrast, olfactory sensory neuron axons project correctly in mice overexpressing wild-type human amyloid precursor protein throughout the brain and in mice overexpressing M671V human APP, a missense mutation that reduces amyloid beta production, exclusively in olfactory sensory neurons. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts the olfactory sensory neuron axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human amyloid beta.
- Published
- 2012
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32. Mice with a "monoclonal nose": perturbations in an olfactory map impair odor discrimination.
- Author
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Fleischmann A, Shykind BM, Sosulski DL, Franks KM, Glinka ME, Mei DF, Sun Y, Kirkland J, Mendelsohn M, Albers MW, and Axel R
- Subjects
- Aggression physiology, Animals, Brain Mapping, Evoked Potentials physiology, Male, Mice, Mice, Transgenic, Olfaction Disorders genetics, Olfaction Disorders metabolism, Olfactory Bulb cytology, Olfactory Bulb physiology, Olfactory Pathways cytology, Olfactory Pathways metabolism, Receptors, Odorant genetics, Sexual Behavior, Animal physiology, Discrimination, Psychological physiology, Nose physiology, Odorants, Olfaction Disorders pathology, Olfactory Receptor Neurons metabolism
- Abstract
We have altered the neural representation of odors in the brain by generating a mouse with a "monoclonal nose" in which greater than 95% of the sensory neurons express a single odorant receptor, M71. As a consequence, the frequency of sensory neurons expressing endogenous receptor genes is reduced 20-fold. We observe that these mice can smell, but odor discrimination and performance in associative olfactory learning tasks are impaired. However, these mice cannot detect the M71 ligand acetophenone despite the observation that virtually all sensory neurons and glomeruli are activated by this odor. The M71 transgenic mice readily detect other odors in the presence of acetophenone. These observations have implications for how receptor activation in the periphery is represented in the brain and how these representations encode odors.
- Published
- 2008
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33. A tale of two etiologies: loss and recovery of olfactory function.
- Author
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Albers MW and Marder KS
- Subjects
- Biomarkers analysis, Disease Progression, Early Diagnosis, Humans, Nerve Regeneration, Parkinson Disease diagnosis, Predictive Value of Tests, Prognosis, Recovery of Function, Stem Cells, Brain physiopathology, Olfaction Disorders etiology, Olfaction Disorders physiopathology, Olfactory Pathways physiopathology, Parkinson Disease complications, Parkinson Disease physiopathology
- Published
- 2008
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34. Validation and optimization of statistical approaches for modeling odorant-induced fMRI signal changes in olfactory-related brain areas.
- Author
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Tabert MH, Steffener J, Albers MW, Kern DW, Michael M, Tang H, Brown TR, and Devanand DP
- Subjects
- Adult, Brain Mapping methods, Cues, Female, Humans, Male, Models, Statistical, Reference Values, Respiration, Magnetic Resonance Imaging methods, Olfactory Bulb anatomy & histology, Olfactory Bulb physiology, Smell physiology
- Abstract
Recent neuroimaging studies have converged to show that odorant-induced responses to prolonged stimulation in primary olfactory cortex (POC) are characterized by a rapidly habituating time course. Different statistical approaches have effectively modeled this time course. One approach explicitly modeled rapid habituation using an exponentially decaying reference waveform that decreased to baseline levels within 30 to 40 s. A second approach modeled an early transient response by simply shortening the odorant 'ON' period to be less than the actual stimulation period (i.e., 9 of 40 s). The goal of the current study was to validate, compare, and optimize these methodological approaches by applying them to an olfactory fMRI block-design dataset from 10 healthy young subjects presented with odorants for 12 s (ON), alternating with 30 s of clear air (OFF). Both approaches significantly improved sensitivity to odorant-induced signal changes in POC relative to a square-wave model based on the actual stimulation period. Our findings further demonstrate that the 'optimal' model fit to the data was achieved by shortening the odorant 'ON' period to approximately 6 s. These results suggest that sensitivity to odorant-induced POC activity in block-design experiments can be optimized by modeling an early phasic response followed by a precipitous rather than specific exponential decrease to baseline levels. Notably, whole brain voxel-wise analyses further established that modeling rapid habituation in this way is not only sensitive, but also highly specific to odorant-induced activation in a well-established network of olfactory-related brain areas.
- Published
- 2007
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35. Olfactory dysfunction as a predictor of neurodegenerative disease.
- Author
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Albers MW, Tabert MH, and Devanand DP
- Subjects
- Animals, Dementia diagnosis, Dementia physiopathology, Humans, Models, Neurological, Nerve Net pathology, Neurofibrillary Tangles pathology, Parkinson Disease diagnosis, Parkinson Disease physiopathology, Predictive Value of Tests, Neurodegenerative Diseases diagnosis, Neurodegenerative Diseases physiopathology, Olfaction Disorders physiopathology
- Abstract
Olfactory dysfunction is present in patients diagnosed with Alzheimer's disease or idiopathic Parkinson's disease and can differentiate each of these disorders from related disorders with similar clinical presentations. The pathologic hallmarks of each disease are present in brain regions involved in processing olfactory input. Both the olfactory functional deficits and the corroborating pathologic lesions are present in asymptomatic subjects with increased risk of developing these diseases. Preclinical detection of neurodegenerative diseases is necessary to control their devastating effects on individuals and societies. We address whether olfactory dysfunction can be used to assess risk for developing Alzheimer's disease or Parkinson's disease in asymptomatic individuals. We argue that further characterization and a deeper understanding of olfactory deficits in these neurodegenerative diseases at the molecular, cellular, and systems levels will augment our acumen for preclinical detection and elucidate pathogenic mechanisms to guide the development of new therapeutic modalities.
- Published
- 2006
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36. HIV encephalitis simulating Huntington's disease.
- Author
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Sevigny JJ, Chin SS, Milewski Y, Albers MW, Gordon ML, and Marder K
- Subjects
- AIDS Dementia Complex immunology, AIDS Dementia Complex pathology, Diagnosis, Differential, Fatal Outcome, Female, Humans, Huntington Disease immunology, Huntington Disease pathology, Immunoglobulin G immunology, Magnetic Resonance Imaging, Microglia immunology, Microglia pathology, Middle Aged, Neural Conduction physiology, Risk Factors, AIDS Dementia Complex complications, Huntington Disease etiology
- Abstract
Complications from human immunodeficiency virus (HIV)/acquired immune deficiency syndrome are notorious for mimicking other neurological diseases. We describe a case of HIV encephalitis presenting with the classic clinical features of Huntington's Disease in a woman without known HIV risk factors or other clinical stigmata suggestive of immunosuppression. This case reminds us that HIV should be part of the differential diagnosis in unexplainable neurological diseases., (Copyright 2004 Movement Disorder Society.)
- Published
- 2005
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37. Potentiation of progesterone receptor-mediated transcription by the immunosuppressant FK506.
- Author
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Tai PK, Albers MW, McDonnell DP, Chang H, Schreiber SL, and Faber LE
- Subjects
- Calcineurin, Calmodulin-Binding Proteins physiology, Carrier Proteins physiology, Gene Expression Regulation drug effects, Heat-Shock Proteins physiology, Imidazoles pharmacology, Phosphoprotein Phosphatases physiology, Polyenes pharmacology, Saccharomyces cerevisiae genetics, Signal Transduction, Sirolimus, Tacrolimus analogs & derivatives, Tacrolimus chemistry, Tacrolimus Binding Proteins, Transcriptional Activation, Receptors, Progesterone physiology, Tacrolimus pharmacology, Transcription, Genetic drug effects
- Abstract
The nontransformed steroid receptors contain several non-steroid binding proteins, such as hsp90, hsp70, and p59. Recently, we and others have shown that p59 (FKBP59) is an immunophilin which binds two potent immunosuppressants, FK506 and rapamycin. This raises the possibility that FK506 or rapamycin may modify the function of steroid receptors. To develop this line of inquiry, we chose a yeast model system in which the human progesterone receptor form B (hPR-B) was cotransformed with a reporter gene. The reporter contains two copies of a progesterone response element/glucocorticoid response element (PRE/GRE) upstream of the CYC1 promoter which are linked to the lacZ gene of Escherichia coli. We found that FK506 potentiated the ability of progesterone in activating transcription. To gain insight into the mechanism of FK506's regulation of PR action, we questioned whether calcineurin is involved, because it has been shown that FK506 is a specific inhibitor of calcineurin, a Ca(2+)- and calmodulin-regulated phosphatase, through the formation of an FKBP12-FK506-calcineurin-calmodulin complex. We found that 15-O-desmethyl-FK520, an FK506 analogue which is an excellent ligand of FKBP12, but a poor inhibitor of calcineurin, failed to induce the same effect as FK506. We also found that calmidazolium, a calmodulin antagonist, mimicked FK506's action. Furthermore, immunoblot analysis showed that both FK506 and calmidazolium potentiated the effect of progesterone in decreasing the mobility of hPR-B upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This suggests that FK506 and calmidazolium may cooperate with progesterone in increasing the level of hPR-B phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
- Full Text
- View/download PDF
38. A mammalian protein targeted by G1-arresting rapamycin-receptor complex.
- Author
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Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, and Schreiber SL
- Subjects
- Amino Acid Sequence, Animals, Carrier Proteins analysis, Carrier Proteins chemistry, Carrier Proteins genetics, Cattle, Cell Cycle Proteins, Cell Line, Cloning, Molecular, DNA, Complementary, Fungal Proteins genetics, Humans, Molecular Sequence Data, Phosphotransferases (Alcohol Group Acceptor) genetics, Polyenes pharmacology, Proteins chemistry, Proteins genetics, Recombinant Fusion Proteins genetics, Saccharomyces cerevisiae genetics, Sequence Homology, Amino Acid, Sirolimus, TOR Serine-Threonine Kinases, Tacrolimus Binding Proteins, Carrier Proteins metabolism, G1 Phase drug effects, Heat-Shock Proteins metabolism, Immunophilins, Phosphatidylinositol 3-Kinases, Polyenes metabolism, Proteins analysis, Saccharomyces cerevisiae Proteins
- Abstract
The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.
- Published
- 1994
- Full Text
- View/download PDF
39. Light-regulated, tissue-specific immunophilins in a higher plant.
- Author
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Luan S, Albers MW, and Schreiber SL
- Subjects
- Amino Acid Isomerases isolation & purification, Amino Acid Isomerases radiation effects, Carrier Proteins radiation effects, Chloroplasts chemistry, Chloroplasts radiation effects, Chromatography, Affinity, Cyclophilin C, Fabaceae radiation effects, Heat-Shock Proteins radiation effects, Light, Peptidylprolyl Isomerase, Tacrolimus Binding Proteins, Tissue Distribution, Carrier Proteins isolation & purification, Cyclophilins, Fabaceae chemistry, Heat-Shock Proteins isolation & purification, Plants, Medicinal, Tacrolimus metabolism
- Abstract
In addition to their application in organ transplantation, immunosuppressive drugs are valuable tools for studying signal transduction in eukaryotic cells. Using affinity chromatography, we have purified immunosuppressive drug receptors (immunophilins) from fava bean. Proteins belonging to both major classes of the immunophilin family identified from animal sources [FK506- and rapamycin-binding proteins (FKBPs) and cyclophilins] were present in this higher plant. FKBP13, the most abundant FKBP family member in leaf tissues, was not detected in root tissues, whereas other FKBPs were present in both tissues. While the abundance of cyclophilin A in leaves was similar to that in roots, cyclophilin B/C was expressed at a much higher level in leaf tissues than in root tissues. Subcellular localization of immunophilins in mesophyll cells showed that chloroplasts contained FKBP13 and cyclophilin B/C but not other members, which explains the preferential expression of these two proteins in leaves over roots. The abundance of chloroplast-localized immunophilins, FKBP13 and cyclophilin B/C, was regulated by light. Although etiolated leaves produced detectable levels of cyclophilin B/C, they did not express FKBP13. Illumination of etiolated plants dramatically increased the expression of both FKBP13 and cyclophilin B/C. The light-induced expression of FKBP13 is closely correlated with the accumulation of chlorophyll in the leaf tissue. Our findings suggest that FKBP13 and cyclophilin B/C may play a specific role in chloroplasts.
- Published
- 1994
- Full Text
- View/download PDF
40. An FKBP-rapamycin-sensitive, cyclin-dependent kinase activity that correlates with the FKBP-rapamycin-induced G1 arrest point in MG-63 cells.
- Author
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Albers MW, Brown EJ, Tanaka A, Williams RT, Hall FL, and Schreiber SL
- Subjects
- Animals, Humans, Mice, Osteosarcoma enzymology, Osteosarcoma pathology, Ribosomal Protein S6 Kinases, Sirolimus, Tacrolimus Binding Proteins, Tumor Cells, Cultured, Carrier Proteins pharmacology, Cyclins physiology, G1 Phase drug effects, Heat-Shock Proteins pharmacology, Immunosuppressive Agents pharmacology, Polyenes pharmacology, Protein Serine-Threonine Kinases physiology
- Published
- 1993
- Full Text
- View/download PDF
41. FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts.
- Author
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Smith DF, Albers MW, Schreiber SL, Leach KL, and Deibel MR Jr
- Subjects
- Animals, Carrier Proteins immunology, Chickens, Chromatography, Affinity, Cross Reactions, Electrophoresis, Gel, Two-Dimensional, HeLa Cells, Heat-Shock Proteins immunology, Humans, Receptors, Progesterone chemistry, Tacrolimus Binding Proteins, Carrier Proteins metabolism, Heat-Shock Proteins metabolism, Receptors, Progesterone metabolism, Tacrolimus metabolism
- Abstract
Avian progesterone receptor complexes contain five major co-purifying proteins, including hsp90, hsp70, and a 23-kDa protein. The other receptor-associated proteins, p50 and p54, share amino acid sequence similarities with a 52-59-kDa component (p59, hsp56, or FKBP52) of mammalian steroid receptor complexes that is also a member of the FK506-binding proteins (FKBP) family of immunophilins. We show here that p50, but not p54, cross-reacts with a rabbit antiserum prepared against human FKBP52. Both p50 and p54 bind an FK506 affinity resin at 0.5 M KCl, but only p50 binds efficiently in low salt conditions. Glycerol density gradient analyses show that both p50 and p54 exist predominantly in oligomeric complexes at low ionic strength. The poor retention of p54 on FK506 resin at low ionic strength compared with the high retention of p50 suggests that these proteins may largely exist in separate complexes and may interact with other proteins, such as progesterone receptor, in distinctive manners. In HeLa cell extracts, a 55-kDa FK506-binding protein, distinct from FKBP52, cross-reacts with anti-p54 antibody FF1. We conclude that p50 is avian FKBP52, whereas p54 and the 55-kDa human FF1 antigen are FKBP54, a novel immunophilin.
- Published
- 1993
42. FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line.
- Author
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Albers MW, Williams RT, Brown EJ, Tanaka A, Hall FL, and Schreiber SL
- Subjects
- Cyclin-Dependent Kinase 2, G1 Phase drug effects, Humans, Osteosarcoma, Protamine Kinase antagonists & inhibitors, Protein Binding, S Phase drug effects, Sirolimus, Tacrolimus Binding Proteins, Tumor Cells, Cultured, CDC2-CDC28 Kinases, Carrier Proteins pharmacology, Cyclin-Dependent Kinases, Cyclins antagonists & inhibitors, Heat-Shock Proteins pharmacology, Immunosuppressive Agents pharmacology, Polyenes pharmacology, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases
- Abstract
Upon entering a cell the natural product rapamycin, like the structurally related immunosuppressant FK506, associates with members of the FKBP family of proteins. One or more of the resulting FKBP-rapamycin complexes blocks signaling pathways emanating from some growth factor receptors. Recently, the addition of rapamycin was shown to inhibit the phosphorylation and activation of a 70-kDa ribosomal S6 protein kinase, which normally occurs minutes after the activation of certain cytokine and growth factor receptors. We now report that rapamycin can be added 4 to 6 h after the addition of serum growth factors to quiescent human osteosarcoma cells and still arrest these cells in G1. This window of action correlates with the inducible appearance of a cyclin-dependent kinase (cdk) activity, and the induction of this activity is inhibited by the addition of rapamycin. Furthermore, p36cyclin D1 associates with this cdk protein complex in lysates of untreated cells, but does not associate with this cdk protein complex in lysates of rapamycin-treated cells. Together, these studies demonstrate that FKBP-rapamycin can modulate a cyclin-dependent kinase activity and a cyclin D1-cdk association during early G1 in MG-63 human osteosarcoma cells.
- Published
- 1993
43. P59 (FK506 binding protein 59) interaction with heat shock proteins is highly conserved and may involve proteins other than steroid receptors.
- Author
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Tai PK, Chang H, Albers MW, Schreiber SL, Toft DO, and Faber LE
- Subjects
- Actins metabolism, Animals, Cells, Cultured, Chickens, Female, Immunosuppressive Agents metabolism, Oviducts metabolism, Protein Binding, Rabbits, Saccharomyces cerevisiae metabolism, Tacrolimus Binding Proteins, Uterus metabolism, Carrier Proteins metabolism, Heat-Shock Proteins metabolism, Receptors, Steroid metabolism, Tacrolimus
- Abstract
P59 [also known as FK506 binding protein 59 (FKBP59) or heat shock protein 56 (hsp56)] and heat shock proteins 90 and 70 (hsp90 and hsp70) associate with steroid receptors and are believed to maintain the receptors in an inactive state. Recently, we showed that p59 purified from human lymphocytes is an immunophilin (FKBP59) which binds both FK506 and rapamycin. It was also demonstrated that immunosuppressant-FKBP59 complexes associate with hsp90, hsp70, and the glucocorticoid receptor [Tai, P.-K. K., Albers, M. W., Chang, H., Faber, L. E., & Schreiber, S. L. (1992) Science 256, 1315-1318]. Here we provide evidence that rabbit uterine p59 also binds FK506 and rapamycin and that p59 or its homologue is associated with nontransformed progesterone receptors of rabbit uterus and chicken oviduct. This suggests that the immunophilin-heat shock protein-steroid receptor interaction is ubiquitous and not limited to immune systems. A FKBP59 homologue complexed with hsp90-hsp70 was also detected in yeast, which suggests that the immunophilin-heat shock protein association has been evolutionarily conserved. In addition, we found that the FKBP59-hsp complexes are more complicated than previously thought, involving other proteins such as actin and a 63-kDa protein, p63. The association of p63 to the p59 complex was inhibited by FK506 and rapamycin, suggesting that p63 could be a potential target for the immunosuppressive actions of these two drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
- Full Text
- View/download PDF
44. Effects of cyclosporin A and FK506 on Fc epsilon receptor type I-initiated increases in cytokine mRNA in mouse bone marrow-derived progenitor mast cells: resistance to FK506 is associated with a deficiency in FK506-binding protein FKBP12.
- Author
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Kaye RE, Fruman DA, Bierer BE, Albers MW, Zydowsky LD, Ho SI, Jin YJ, Castells MC, Schreiber SL, and Walsh CT
- Subjects
- Amino Acid Isomerases metabolism, Animals, Bone Marrow Cells, Calcineurin, Calmodulin-Binding Proteins metabolism, Exocytosis drug effects, Gene Expression drug effects, Mast Cells cytology, Mice, Peptidylprolyl Isomerase, Phosphoprotein Phosphatases metabolism, Phosphoric Monoester Hydrolases metabolism, RNA, Messenger genetics, Receptors, IgE, Tacrolimus Binding Proteins, beta-N-Acetylhexosaminidases metabolism, Antigens, Differentiation, B-Lymphocyte physiology, Carrier Proteins metabolism, Cyclosporine pharmacology, Cytokines genetics, Mast Cells immunology, Receptors, Fc physiology, Tacrolimus pharmacology
- Abstract
The inhibitory effects of cyclosporin A (CsA) and FK506 on Fc epsilon receptor type I-initiated increases in cytokine mRNA and the expression of their intracellular binding proteins were studied in interleukin 3 (IL-3)-dependent, mouse bone marrow-derived mast cells (BMMCs). In BMMCs sensitized with IgE anti-trinitrophenyl, CsA inhibited trinitrophenylated bovine serum albumin-induced increases in mRNA for IL-1 beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 in a dose-related manner (IC50 values of 4, 65, and 130 nM, respectively). FK506 did not inhibit hapten-specific increases of mRNA for TNF-alpha or IL-6, and for IL-1 beta the IC50 was greater than 50-fold higher than that of CsA. Neither agent inhibited exocytosis of the endogenous secretory granule mediators beta-hexosaminidase and histamine at the IC50 values for inhibition of increases in cytokine mRNA. BMMCs expressed cyclophilin, and CsA inhibited the phosphatase activity of cellular calcineurin with an IC50 of approximately 8 nM. That CsA inhibited IL-1 beta mRNA accumulation in IgE-activated BMMCs with an IC50 similar to that for inhibition of calcineurin activity, whereas the IC50 values were approximately 20-fold higher for the inhibition of TNF-alpha and IL-6 mRNA, suggests that the induction of TNF-alpha and IL-6 is less dependent upon calcineurin activity than is the induction of IL-1 beta. BMMCs were deficient in the 12-kDa FK506-binding protein FKBP12, but not FKBP13, as assessed by RNA and protein blot analyses. FK506 did not inhibit calcineurin phosphatase activity in BMMCs, even at drug concentrations of 1000 nM. The resistance of BMMCs to inhibition of Fc epsilon receptor type I-mediated increases in cytokine mRNA by FK506 is most likely due to their deficiency of FKBP12 and the related inability to inhibit the activity of calcineurin.
- Published
- 1992
- Full Text
- View/download PDF
45. Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex.
- Author
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Tai PK, Albers MW, Chang H, Faber LE, and Schreiber SL
- Subjects
- Amino Acid Isomerases isolation & purification, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Carrier Proteins isolation & purification, Cell Line, Heat-Shock Proteins isolation & purification, Humans, Kinetics, Macromolecular Substances, Molecular Sequence Data, Molecular Weight, Peptidylprolyl Isomerase, Polyenes metabolism, Rats, Receptors, Glucocorticoid isolation & purification, Sequence Homology, Nucleic Acid, Sirolimus, Tacrolimus metabolism, Tacrolimus Binding Proteins, Amino Acid Isomerases metabolism, Carrier Proteins metabolism, Heat-Shock Proteins metabolism, Receptors, Glucocorticoid metabolism
- Abstract
Immunophilins, a family of proteins that exhibit rotamase (peptidyl-prolyl cis-trans isomerase) activity in vitro, are expressed in many organisms and most tissues. Although some immunophilins can mediate the immunosuppressive actions of FK506, rapamycin, and cyclosporin A, the physiological role of the unligated proteins is not known. A 59-kilodalton member of the FK506- and rapamycin-binding class was found to associate in the absence of these drugs with two heat shock proteins (hsp90 and hsp70) and the glucocorticoid receptor (GR). Together, these proteins make up the inactive GR, thus biochemically linking two families of proteins proposed to be involved in protein folding and assembly as well as two potent immunosuppressive modalities.
- Published
- 1992
- Full Text
- View/download PDF
46. Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity.
- Author
-
Liu J, Albers MW, Wandless TJ, Luan S, Alberg DG, Belshaw PJ, Cohen P, MacKintosh C, Klee CB, and Schreiber SL
- Subjects
- Amino Acid Sequence, Calcineurin, Calmodulin-Binding Proteins metabolism, Carrier Proteins pharmacology, Cyclosporine metabolism, Cyclosporine pharmacology, Cyclosporins chemistry, Cyclosporins metabolism, Humans, Molecular Sequence Data, Molecular Structure, Peptide Fragments antagonists & inhibitors, Peptide Fragments metabolism, Phosphoprotein Phosphatases metabolism, Tacrolimus analogs & derivatives, Tacrolimus metabolism, Calmodulin-Binding Proteins antagonists & inhibitors, Carrier Proteins metabolism, Cyclosporins pharmacology, Phosphoprotein Phosphatases antagonists & inhibitors, Signal Transduction drug effects, T-Lymphocytes physiology, Tacrolimus pharmacology
- Abstract
Calcineurin, a Ca2+, calmodulin-dependent protein phosphatase, was recently found to bind with high affinity to two different immunosuppressant binding proteins (immunophilins) with absolute dependence on the presence of the immunosuppressants FK506 or cyclosporin A (CsA) [Liu et al. (1991) Cell 66, 807-815]. The binding affinities of the immunophilin-drug complexes toward calcineurin and the stoichiometry of the resultant multimeric complexes have now been determined, and structural elements of FK506, CsA, and calcineurin that are critical for mediating their interactions have been identified. Analogues of FK506 (FK520, FK523, 15-O-demethyl-FK520) and CsA (MeBm2t1-CsA and MeAla6-CsA) whose affinities for their cognate immunophilins do not correlate with their immunosuppressive activities have been prepared and evaluated in biochemical and cellular assays. We demonstrate a strong correlation between the ability of these analogues, when bound to their immunophilins, to inhibit the phosphatase activity of calcineurin and their ability to inhibit transcriptional activation by NF-AT, a T cell specific transcription factor that regulates IL-2 gene synthesis in human T cells. In addition, FKBP-FK506 and CyP-CsA do not inhibit members of the PP1, PP2A, and PP2C classes of serine/threonine phosphatases. These data suggest that calcineurin is the relevant cellular target of these immunosuppressive agents and is involved in Ca(2+)-dependent signal transduction pathways in, among others, T cells and mast cells.
- Published
- 1992
- Full Text
- View/download PDF
47. Immunophilin-ligand complexes as probes of intracellular signaling pathways.
- Author
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Schreiber SL, Liu J, Albers MW, Karmacharya R, Koh E, Martin PK, Rosen MK, Standaert RF, and Wandless TJ
- Subjects
- Animals, Cell Division drug effects, Cyclosporine chemistry, Cyclosporine metabolism, Cyclosporine pharmacology, Exocytosis drug effects, Humans, Immunosuppressive Agents metabolism, Ligands, Models, Biological, Models, Molecular, Molecular Conformation, Polyenes metabolism, Polyenes pharmacology, Sirolimus, Tacrolimus chemistry, Tacrolimus metabolism, Tacrolimus pharmacology, Transcription, Genetic drug effects, Carrier Proteins metabolism, Immunosuppressive Agents pharmacology, Signal Transduction drug effects
- Published
- 1991
48. Hepatotrophic properties in dogs of human FKBP, the binding protein for FK506 and rapamycin.
- Author
-
Starzl TE, Schreiber SL, Albers MW, Porter KA, Foglieni CS, and Francavilla A
- Subjects
- Animals, Cloning, Molecular, Dogs, Electrophoresis, Polyacrylamide Gel, Humans, Recombinant Proteins pharmacology, Sirolimus, Sodium Dodecyl Sulfate, Tacrolimus Binding Proteins, Carrier Proteins pharmacology, Immunosuppressive Agents metabolism, Liver Regeneration drug effects, Polyenes metabolism, Tacrolimus metabolism
- Published
- 1991
- Full Text
- View/download PDF
49. Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13.
- Author
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Jin YJ, Albers MW, Lane WS, Bierer BE, Schreiber SL, and Burakoff SJ
- Subjects
- Amino Acid Sequence, Antifungal Agents metabolism, Base Sequence, Blotting, Northern, Carrier Proteins metabolism, Cell Line, Cloning, Molecular methods, Humans, Immunosuppressive Agents metabolism, Models, Molecular, Molecular Sequence Data, Polymerase Chain Reaction, Protein Conformation, RNA, Messenger analysis, RNA, Messenger genetics, Sequence Homology, Nucleic Acid, Sirolimus, Tacrolimus, Anti-Bacterial Agents metabolism, Carrier Proteins genetics, Polyenes metabolism, Tacrolimus Binding Proteins
- Abstract
The 12-kDa FK506-binding protein (FKBP-12) is a cytosolic receptor for the immunosuppressants FK506 and rapamycin. Here we report the molecular cloning and subcellular localization of a 13-kDa FKBP (FKBP-13), which has a 21-amino acid signal peptide and appears to be membrane-associated. Although no internal hydrophobic region, and thus no transmembrane domain, is apparent within the 120 amino acids of mature FKBP-13, a potential endoplasmic reticulum retention sequence (Arg-Thr-Glu-Leu) is found at its C terminus. FKBP-13 has 51% nucleotide sequence identity and 43% amino acid sequence identity to FKBP-12; the N-terminal sequences are divergent, but the 92-amino acid C-terminal sequence of FKBP-13 has 46 identical and 20 related residues when compared with FKBP-12. The conserved residues that comprise the drug binding site and rotamase active site of FKBP-12 are completely conserved in FKBP-13. Therefore, the three-dimensional structures of FKBP-12 and the FKBP-12/FK506 complex are likely to be excellent models of the corresponding FKBP-13 structure.
- Published
- 1991
- Full Text
- View/download PDF
50. Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.
- Author
-
Hultsch T, Albers MW, Schreiber SL, and Hohman RJ
- Subjects
- Animals, Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Arachidonic Acids metabolism, Calcium metabolism, Cell Line, Cyclosporins metabolism, Cyclosporins pharmacology, Immunoglobulin E immunology, Kinetics, Ligands, Phosphatidylinositols metabolism, Polyenes metabolism, Polyenes pharmacology, Rats, Receptors, Fc drug effects, Receptors, IgE, Serotonin metabolism, Sirolimus, Tacrolimus, Antigens, Differentiation, B-Lymphocyte physiology, Carrier Proteins metabolism, Exocytosis drug effects, Immunosuppressive Agents pharmacology, Receptors, Fc physiology, Signal Transduction drug effects, Transcription, Genetic drug effects
- Abstract
Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsA-binding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC50 = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca2+). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism.
- Published
- 1991
- Full Text
- View/download PDF
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