Your search for: 'author:("Hyman, Bradley T.")' has returned 9 results. (0.015s) Save search

Authors: Saidi, Laiq-Jan | Polydoro, Manuela | Kay, Kevin R. | Sanchez, Laura | Mandelkow, Eva-Maria | Hyman, Bradley T. | Spires-Jones, Tara L.

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease is the formation of neurofibrillary tangles, intracellular aggregates of hyperphosphorylated, mislocalized tau protein, which are associated with neuronal loss. Changes in tau are known to impair cellular transport (including that of mitochondria) and are associated with cell death in cell culture and mouse models of tauopathy. Thus clearing pathological forms of tau from cells is a key therapeutic strategy. One critical modulator in the degradation and clearance of misfolded proteins is the co-chaperone CHIP (Carboxy terminus Hsp70 interacting Protein), which is known to play a role in refolding and clearance of hyperphosphorylated tau. …Here, we tested the hypothesis that CHIP could ameliorate pathological changes associated with tau. We find that co-expressing CHIP with full-length tau, tau truncated at D421 mimicking caspase cleavage, or the short tauRD ΔK280 tau construct containing only the tau repeat domain with a tauopathy mutation, decreases tau protein levels in human H4 neuroglioma cells in a manner dependent on the Hsp70-binding TPR domain of CHIP. The observed reduction in tau levels by CHIP is associated with a decrease of tau phosphorylation and reduced levels of cleaved Caspase 3 indicating that CHIP plays an important role in preventing tau-induced pathological changes. Furthermore, tau-associated mitochondrial transport deficits are rescued by CHIP co-expression in H4 cells. Together, these data suggest that the co-chaperone CHIP can rescue the pathological effects of tau, and indicate that other diseases of protein misfolding and accumulation may also benefit from CHIP upregulation. Show more

Keywords: Alzheimer's disease, caspase, CHIP, mitochondrial transport, tau protein

DOI: 10.3233/JAD-142094

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 937-947, 2015

Authors: Noori, Ayush | Jayakumar, Rojashree | Moturi, Vaishnavi | Li, Zhaozhi | Liu, Rongxin | Serrano-Pozo, Alberto | Hyman, Bradley T. | Das, Sudeshna

Article Type: Research Article

Abstract: Background: Recent Alzheimer’s disease (AD) discoveries are increasingly based on studies from a variety of omics technologies on large cohorts. Currently, there is no easily accessible resource for neuroscientists to browse, query, and visualize these complex datasets in a harmonized manner. Objective: Create an online portal of public omics datasets for AD research. Methods: We developed Alzheimer DataLENS, a web-based portal, using the R Shiny platform to query and visualize publicly available transcriptomics and genetics studies of AD on human cohorts. To ensure consistent representation of AD findings, all datasets were processed through a uniform bioinformatics pipeline. Results: Alzheimer DataLENS …currently houses 2 single-nucleus RNA sequencing datasets, over 30 bulk RNA sequencing datasets from 19 brain regions and 3 cohorts, and 2 genome-wide association studies (GWAS). Available visualizations for single-nucleus data include bubble plots, heatmaps, and UMAP plots; for bulk expression data include box plots and heatmaps; for pathways include protein-protein interaction network plots; and for GWAS results include Manhattan plots. Alzheimer DataLENS also links to two other knowledge resources: the AD Progression Atlas and the Astrocyte Atlas. Conclusions: Alzheimer DataLENS is a valuable resource for investigators to quickly and systematically explore omics datasets and is freely accessible at https://alzdatalens.partners.org . Show more

Keywords: Alzheimer’s disease, database, genetics, multiomics, single-cell RNA-seq, transcriptomics

DOI: 10.3233/JAD-230884

Citation: Journal of Alzheimer's Disease, vol. 99, no. s2, pp. S397-S407, 2024

Authors: Mezlini, Aziz M. | Magdamo, Colin | Merrill, Emily | Chibnik, Lori B. | Blacker, Deborah L. | Hyman, Bradley T. | Das, Sudeshna

Article Type: Research Article

Abstract: Background: The APOE ɛ 4 allele is the largest genetic risk factor for late-onset Alzheimer’s disease (AD). Recent literature suggested that the contribution of APOE ɛ 4 to AD risk could be population-specific, with ɛ 4 conferring a lower risk to Blacks or African Americans. Objective: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA). Methods: We selected data from 1) the National Alzheimer’s Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer’s Disease Genetics Consortium (ADGC), …and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ 3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU. Results: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ 4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOE ɛ 4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ 4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification. Conclusion: Our study finds similar effects of the ɛ 4-linked haplotypes defined by rs769449 on AD as compared to ɛ 3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations. Show more

Keywords: African Americans, APOE, clinicopathological features, Europeans, genotype

DOI: 10.3233/JAD-200228

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 467-477, 2020

Authors: Marshall, Gad A. | Lorius, Natacha | Locascio, Joseph J. | Hyman, Bradley T. | Rentz, Dorene M. | Johnson, Keith A. | Sperling, Reisa A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver. Objective: To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods: Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer’s Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional …Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed. Results: IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p < 0.0001), greater lateral occipital cortical thickness and diagnosis (p < 0.0001), and greater amyloid-β 1-42 (Aβ1-42 ) and diagnosis (p = 0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p = 0.02) and inferior temporal (p = 0.05) cortical thickness, lower Aβ1-42 (p < 0.0001), and greater total tau (t-tau) (p = 0.02) were associated with greater rate of IADL impairment over time. Conclusions: Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42 , and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, instrumental activities of daily living, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-132768

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 719-728, 2014

Authors: Ren, Yan | Lin, Wen-Lang | Sanchez, Laura | Ceballos, Carolina | Polydoro, Manuela | Spires-Jones, Tara L. | Hyman, Bradley T. | Dickson, Dennis W. | Sahara, Naruhiko

Article Type: Research Article

Abstract: Tau belongs to the microtubule-associated family of proteins that maintain cytoskeletal structure by regulating microtubule dynamics. In certain neurodegenerative diseases termed tauopathies, tau is abnormally phosphorylated and accumulates as filamentous inclusions. Transgenic mouse models that overexpress human tau have been widely used to investigate tau pathogenesis. Although many studies have attempted to elucidate the pathological function of transgenic human tau, it remains unknown whether endogenous mouse tau is involved in disease progression. Here we generated an mTau antibody that selectively recognizes mouse and rat tau, but not human tau. In rTg4510 tau transgenic mice, we identified a higher molecular weight …mouse tau (~60-kDa) in sarkosyl-insoluble fractions. mTau antibody started to recognize intracellular aggregates and thread-like structures in 4- to 6-month-old rTg4510 mice. Tau inclusions appeared earlier, being detected in 2.5-month-old rTg4510 mice with MC1 antibody. Immunoelectron microscopy confirmed the presence of filamentous aggregates of mouse tau, which were abundant in oligodendrocytes but rare in neurons. Mouse tau inclusions in oligodendrocytes were confirmed by double-labeling with an oligodendrocyte marker. Our data indicate that mouse tau has potential aggregation properties in neurons and non-neurons. The mTau antibody will be useful for investigating the role of mouse tau in mouse models of tauopathy. Show more

Keywords: Antibody, mouse tau, oligodendrocytes, tau protein, tauopathy, transgenic mice

DOI: 10.3233/JAD-130986

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 589-600, 2014

Authors: Bakshi, Rachit | Macklin, Eric A. | Hung, Albert Y. | Hayes, Michael T. | Hyman, Bradley T. | Wills, Anne-Marie | Gomperts, Stephen N. | Growdon, John H. | Ascherio, Alberto | Scherzer, Clemens R. | Schwarzschild, Michael A.

Article Type: Short Communication

Abstract: Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson’s disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these ‘reduced risk’ factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean …difference –125 mg/day, p  < 0.001) but not in females (mean difference –30 mg/day, p  = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference –0.46 mg/dL, p  = 0.017) and females (mean difference –0.45 mg/dL, p  = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD. Show more

Keywords: Caffeine, uric acid, biomarker, Parkinson’s disease

DOI: 10.3233/JPD-191882

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 505-510, 2020

Authors: Dumurgier, Julien | Hanseeuw, Bernard J. | Hatling, Frances B. | Judge, Kelly A. | Schultz, Aaron P. | Chhatwal, Jasmeer P. | Blacker, Deborah | Sperling, Reisa A. | Johnson, Keith A. | Hyman, Bradley T. | Gómez-Isla, Teresa

Article Type: Research Article

Abstract: Background: Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer’s disease (AD) modifying therapies move toward preclinical stages. Objective: To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults. Methods: 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer’s Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of amyloid-β 1–42 (Aβ42 ), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) in the cerebrospinal fluid (CSF) at study entry were available …in all cases. Baseline brain MRI, FDG-PET, and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models. Results: 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention, and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score. Conclusions: Baseline CSF t-Tau and p-Tau181, in vivo amyloid load, and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest. Show more

Keywords: Biomarkers, cognitive decline, cerebrospinal fluid, epidemiology, neuroimaging

DOI: 10.3233/JAD-170511

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1451-1459, 2017

Authors: Pickett, Eleanor K. | Koffie, Robert M. | Wegmann, Susanne | Henstridge, Christopher M. | Herrmann, Abigail G. | Colom-Cadena, Marti | Lleo, Alberto | Kay, Kevin R. | Vaught, Melissa | Soberman, Roy | Walsh, Dominic M. | Hyman, Bradley T. | Spires-Jones, Tara L.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron …microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue. Show more

Keywords: Alzheimer’s disease, amyloid-β, array tomography, synapses

DOI: 10.3233/JAD-160007

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 787-800, 2016

Authors: Petrozziello, Tiziana | Huntress, Sommer S. | Castillo-Torres, Ayleen L. | Quinn, James P. | Connors, Theresa R. | Auger, Corinne A. | Mills, Alexandra N. | Kim, Spencer E. | Liu, Sophia | Mahmood, Farah | Boudi, Adel | Wu, Muzhou | Sapp, Ellen | Kivisäkk, Pia | Sunderesh, Shekar R. | Pouladi, Mahmoud A. | Arnold, Steven E. | Hyman, Bradley T. | Rosas, H. Diana | DiFiglia, Marian | Mouro Pinto, Ricardo | Kegel-Gleason, Kimberly | Sadri-Vakili, Ghazaleh

Article Type: Research Article

Abstract: Background: To date, it is still controversial whether tau phosphorylation plays a role in Huntington’s disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models. Objective: The goal of this study was to determine whether total tau and pTau levels are altered in HD. Methods: Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic …embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ 111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. Results: Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ 111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. Conclusions: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC. Show more

Keywords: Huntington’s disease, total tau, phosphorylated tau, fractionations, postmortem brain, ESC-derived neurons, neuronal stem cells, mouse models, plasma

DOI: 10.3233/JHD-230588

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 267-281, 2023