Publications
Below you’ll find our complete publication record, including peer-reviewed articles, reviews, and conference proceedings. Google Scholar PubMed
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2022
APOE4 derived from astrocytes leads to blood-brain barrier impairment
Rosemary J. Jackson, Jonah C. Meltzer, Huong Nguyen, Caitlin Commins, Rachel E. Bennett, Eloise Hudry, Bradley T. Hyman (2022)
Brain , Vol. 145 , pp. 3582-3593
Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood-brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood-brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood-brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood-brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood-brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood-brain barrier.
Article APOE4 Blood-Brain Barrier Alzheimer's Disease AstrocytesSomatic genomic changes in single Alzheimer's disease neurons
Michael B. Miller, August Yue Huang, Junho Kim, Zinan Zhou, Samanthan L. Kirkham, Eduardo A. Maury, Jenniger S. Ziegenfuss, Hannah C. Reed, Jennifer E. Neil, Lariza Rento, Steven C. Ryu, Chanthia C. Ma, Lovelace J. Luquette, Heather M. Ames, Derek H. Oakley, Matthew P. Frosch, Bradley T. Hyman, Michael A. Lodato, Eunjung Alice Lee, Christopher A. Walsh (2022)
Nature , Vol. 604 , pp. 714-722
Dementia in Alzheimer’s disease correlates with progressive neurodegeneration, but the precise causes of neuronal dysfunction remain unclear. This study analyzed single-cell whole-genome sequencing of 319 neurons from Alzheimer’s patients and controls, revealing increased somatic DNA mutations in affected neurons with distinct molecular signatures. While normal neurons accumulate mutations via age-related “clock-like” patterns, Alzheimer’s neurons exhibit additional oxidative DNA damage. These mutations affect coding regions and likely disrupt neuronal function, suggesting that genomic damage contributes to disease progression and neuronal impairment.
Article Alzheimer's Disease Neuronal Genomics Somatic Mutations2023
All the Tau We Cannot See Featured
Bradley Hyman (2023)
Annual Review of Medicine , Vol. 74 , pp. 503-514
Alzheimer’s disease (AD) was described in 1906 as a dementing disease marked by the presence of two types of fibrillar aggregates in the brain: neurofibrillary tangles and senile plaques. The process of aggregation and formation of the aggregates has been a major focus of investigation ever since the discoveries that the tau protein is the predominant protein in tangles and amyloid β is the predominant protein in plaques. The idea that smaller, oligomeric species of amyloid may also be bioactive has now been clearly established. This review examines the possibility that soluble, nonfibrillar, bioactive forms of tau—the “tau we cannot see”—comprise a dominant driver of neurodegeneration in AD.
Review Tau Pathology Alzheimer's DiseaseCommon mouse models of tauopathy reflect early but not late human disease
Kathrin Wenger, Arthur Viode, Christoph N. Schlaffner, Patrick van Zalm, Long Cheng, Tammy Dellovade, Xavier Langlois, Anthony Bannon, Rui Chang, Theresa R. Connors, Derek Oakley, Beernhard Renard, Juri Rappsilber, Bradley Hyman, Hanno Steen, Judith A. Steen (2023)
Molecular Neurodegeneration , Vol. 18 , pp. 10
Mouse models that overexpress human mutant Tau (P301S and P301L) are commonly used in preclinical studies of Alzheimer’s Disease (AD) and while several drugs showed therapeutic efects in these mice, they were inefective in humans. This leads to the question to which extent the murine models refect human Tau pathology on the molecular level. AD mouse models that overexpress human Tau using risk mutations are a suitable tool for testing drug candidates that aim to intervene in the early formation of insoluble Tau species promoted by increased phosphorylation of Tau.
Article Tauopathy Mouse Models Alzheimer's DiseaseEndothelial Cells Are Heterogeneous in Different Brain Regions and Are Dramatically Altered in Alzheimer's Disease
Annie Bryant, Zhaozhi Li, Rojashree Jayakumar, Alberto Serrano-Pozo, Benjaminn Woost, Miwei Hu, Maya E. Woodbury, Astrid Wachter, Gen Lin, Taekyung Kwon, Robert V. Talanian, Knut Biber, Eric H. Karran, Bradley T. Hyman, Sudeshna Das, Rachel E. Bennett (2023)
Journal of Neuroscience , Vol. 43 , pp. 4541-4557
Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimer’s disease (AD) is obscured by limited understanding of the cellular heterogeneity in normal aged brain and in disease. To address this, we performed single nucleus RNAseq on tissue from 32 human AD and non-AD donors (19 female, 13 male) each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex, and primary visual cortex. Analysis of 51,586 endothelial cells revealed unique gene expression patterns across the five regions in non-AD donors. Alzheimer’s brain endothelial cells were characterized by upregulated protein folding genes and distinct transcriptomic differences in response to amyloid b plaques and cerebral amyloid angiopathy. This dataset demonstrates previously unrecognized regional heterogeneity in the endothelial cell transcriptome in both aged non-AD and AD brain.
Article Endothelial Cells Brain Heterogeneity Alzheimer's Disease2024
Alzheimer proteopathic tau seeds are biochemically a forme fruste of mature paired helical filaments
Mukesh Kumar, Noé Quittot, Simon Dujardin, Christoph N. Schlaffner, Arthur Viode, Anne Wiedmer, Pieter Beerepoot, Joshua E. Chun, Calina Glynn, Analiese R. Fernandes, Cameron Donahue, Judith A. Steen, Bradley T. Hyman (2024)
Brain , Vol. 147 , pp. 637-648
Aggregation prone molecules, such as tau, form both historically well characterized fibrillar deposits (neurofibrillary tangles) and recently identified phosphate-buffered saline (PBS) extract species called proteopathic seeds. Both can cause normal endogenous tau to undergo templated misfolding. The relationship of these seeds to the fibrils that define tau-related diseases is unknown. We characterized the aqueous extractable and sarkosyl insoluble fibrillar tau species derived from human Alzheimer brain using mass spectrometry and in vitro bioassays. Post-translational modifications (PTMs) including phosphorylation, acetylation and ubiquitination are identified in both preparations. PBS extract seed competent tau can be distinguished from sarkosyl insoluble tau by the presence of overlapping, but less abundant, PTMs and an absence of some PTMs unique to the latter. The presence of ubiquitin and other PTMs on the PBS-extracted tau species correlates with the amount of tau in the seed competent size exclusion fractions, with the bioactivity and with the aggressiveness of clinical disease. These results demonstrate that the PTMs present on bioactive, seed competent PBS extract tau species are closely related to, but distinct from, the PTMs of mature paired helical filaments, consistent with the idea that they are a forme fruste of tau species that ultimately form fibrils.
Article Tau Pathology Alzheimer's DiseaseAPOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease
Rosemary J. Jackson, Megan S. Keiser, Jonah C. Meltzer, Dustin P. Fykstra, Steven E. Dierksmeier, Soroush Hajizadeh, Johannes Kreuzer, Robert Morris, Alexandra Melloni, Tsuneo Nakajima, Luis Tecedor, Paul T. Ranum, Ellie Carrell, YongHong Chen, Maryam A. Nishtar, David M. Holtzman, Wilhelm Haas, Beverly L. Davidson, Bradley T. Hyman (2024)
Molecular Therapy , Vol. 32 , pp. 1373-1386
Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Ab plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.
Article APOE2 Gene Therapy Alzheimer's DiseaseCryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease
Ana R. Agra Almeida Quadros, Zhaozhi Li, Xue Wang, I. Sandra Ndayambaje, Sandeep Aryal, Nandini Ramesh, Matthew Nolan, Rojashree Jayakumar, Yi Han, Hannah Stillman, Corey Aguilar, Hayden J. Wheeler, Theresa Connors, Jone Lopez-Erauskin, Michael W. Baughn, Ze'ev Melamed, Melinda S. Beccari, Laura Olmedo Martínez, Michael Canori, Chao-Zong Lee, Laura Moran, Isabelle Draper, Alan S. Kopin, Derek H. Oakley, Dennis W. Dickson, Don W. Cleveland, Bradley T. Hyman, Sudeshna Das, Nilüfer Ertekin-Taner, Clotilde Lagier-Tourenne (2024)
Acta Neuropathologica , Vol. 147 , pp. 9
Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer’s disease. In Alzheimer’s disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer’s disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer’s disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer’s disease.
Article TDP-43 Cryptic Splicing Alzheimer's DiseaseDistinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease Featured
Sudeshna Das, Zhaozhi Li, Astrid Wachter, Srinija Alla, Ayush Noori, Aicha Abdourahman, Joseph A. Tamm, Maya E. Woodbury, Robert V. Talanian, Knut Biber, Eric H. Karran, Bradley T. Hyman, Alberto Serrano-Pozo (2024)
Alzheimer's & Dementia , Vol. 20 , pp. 74-90
Omics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer’s disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear. We performed laser capture microdissection of amyloid beta (Aβ) plaques, the 50 μm halo around them, tangles with the 50 μm halo around them, and areas distant (> 50 μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing.
Article Transcriptomics Amyloid-beta Plaques Neurofibrillary Tangles APOE Alzheimer's DiseaseLandscape of brain myeloid cell transcriptome along the spatiotemporal progression of Alzheimer's disease reveals distinct sequential responses to Aβ and tau
Astrid Wachter, Maya E. Woodbury, Sylvia Lombardo, Aicha Abdourahman, Carolin Wuest, Emily McGlame, Timothy Pastika, Joseph Tamm, Nandini Romanul, Kiran Yanamandra, Rachel Bennett, Gen Lin, Taekyung Kwon, Fan Liao, Corinna Klein, Yelena Grinberg, Methasit Jaisa-Aad, Huan Li, Matthew P. Frosch, Markus P. Kummer, Sudeshna Das, Tammy Dellovade, Eric H. Karran, Xavier Langlois, Janina Ried, Alberto Serrano-Pozo, Robert V. Talanian, Knut Biber, Bradley T. Hyman (2024)
Acta Neuropathologica , Vol. 147 , pp. 65
Human microglia are critically involved in Alzheimer’s disease (AD) progression, as shown by genetic and molecular studies. However, their role in tau pathology progression in human brain has not been well described. Here, we characterized 32 human donors along progression of AD pathology, both in time-from early to late pathology-and in space-from entorhinal cortex (EC), inferior temporal gyrus (ITG), prefrontal cortex (PFC) to visual cortex (V2 and V1)-with biochemistry, immunohistochemistry, and single nuclei-RNA-sequencing, profiling a total of 337,512 brain myeloid cells, including microglia. While the majority of microglia are similar across brain regions, we identified a specific subset unique to EC which may contribute to the early tau pathology present in this region. We calculated conversion of microglia subtypes to diseased states and compared conversion patterns to those from AD animal models. Targeting genes implicated in this conversion, or their upstream/downstream pathways, could halt gene programs initiated by early tau progression. We used expression patterns of early tau progression to identify genes whose expression is reversed along spreading of spatial tau pathology (EC > ITG > PFC > V2 > V1) and identified their potential involvement in microglia subtype conversion to a diseased state. This study provides a data resource that builds on our knowledge of myeloid cell contribution to AD by defining the heterogeneity of microglia and brain macrophages during both temporal and regional pathology aspects of AD progression at an unprecedented resolution.
Article Myeloid Cells Transcriptomics Alzheimer's Disease Amyloid-beta TauMultifaceted roles of APOE in Alzheimer disease Featured
Rosemary J. Jackson, Bradley T. Hyman, Alberto Serrano-Pozo (2024)
Nature Reviews Neurology , Vol. 20 , pp. 457-474
For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene-environment interactions. Although early studies linked APOE to amyloid-β - one of the two culprit aggregation-prone proteins that define AD - in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood-brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.
Review APOE Alzheimer's DiseaseNeurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer's pathology
Theodore J. Zwang, Eric del Sastre, Nina Wolf, Nancy Ruiz-Uribe, Benjamin Woost, Zachary Hoglund, Zhanyun Fan, Joshua Bailey, Lois Nfor, Luc Buée, K. Peter R. Nilsson, Bradley T. Hyman, Rachel E. Bennett (2024)
Cell Reports , Vol. 43 , pp. 114574
A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline in Alzheimer’s disease (AD) because tangles correlate anatomically with areas that undergo neuronal loss. We used two-photon longitudinal imaging to directly test this hypothesis and observed the fate of individual neurons in two mouse models. At any time point, neurons without tangles died at >3 times the rate as neurons with tangles. Additionally, prior to dying, they became >20% more distant from neighboring neurons across imaging sessions. Similar microstructural changes were evident in a population of non-tangle-bearing neurons in Alzheimer’s donor tissues. Together, these data suggest that nonfibrillar tau puts neurons at high risk of death, and surprisingly, the presence of a tangle reduces this risk. Moreover, cortical microstructure changes appear to be a better predictor of imminent cell death than tangle status is and a promising tool for identifying dying neurons in Alzheimer’s.
Article Neurofibrillary Tangles Alzheimer's Disease Neurodegeneration2025
Alzheimer disease-associated tau post-translational modification mimics impact tau propagation and uptake
John R. Dickson, Robert G. R. Sobolewski, Analise R. Fernandes, Joanna M. Cooper, Zhanyun Fan, Mirra Chung, Cameron Donahue, Derek H. Oakley, Dudley K. Strickland, Bradley T. Hyman (2025)
Journal of Neuropathology & Experimental Neurology , Vol. 84 , pp. 459-470
As Alzheimer disease (AD) progresses, pathological tau spreads by cell-to-cell propagation of tau. This study aims to elucidate the impact of AD-associated post-translational modifications of tau-on-tau propagation. Tau propagation reporter constructs distinguishing donor cells from recipient cells were developed, and additional constructs were made with tau residues mutated from serine or threonine to aspartate to mimic the negative charge of a phosphorylation and/or from lysine to glutamine to mimic the charge-neutralizing effect of acetylation. Flow cytometry was used to quantify donor and recipient cells. This revealed that the mutations generally tended to reduce tau propagation compared to wildtype tau. Recombinant tau containing either wildtype or posttranslational modification mimicking mutations were used to treat Chinese hamster ovary cells or human induced pluripotent stem cell-derived neurons to quantify tau uptake, revealing that the mutations generally resulted in reduced uptake compared to wildtype tau. Surface plasmon resonance revealed that the mutations had a reduced affinity for lipoprotein receptor-related protein 1 (LRP1), a tau uptake receptor, compared to wildtype tau. Overall, these results suggest that AD-associated posttranslational modification mimicking mutations reduce the cell-to-cell propagation of tau by reducing tau uptake by recipient cells, which may be in part due to reduced binding affinity to LRP1.
Article Tau Pathology Alzheimer's Disease Post-translational Modifications NeurodegenerationUbiquitin-Proteasome System Dysregulation in Alzheimer's Disease Impacts Protein Abundance
Mahlon Collins, Corinna Friedrich, Megan Elcheikhali, Peyton Stewart, Jason Derks, Theresa Connors-Stewart, Kirstin Altig, Alexandra Melloni, Aleksandra Petelski, Derek Oakley, Bradley T. Hyman, Nikolai Slavov (2025)
bioRxiv
Alzheimer’s disease (AD) is a relentlessly progressive, fatal neurodegenerative disorder associated with widespread aberrant proteomic changes. The full extent of protein dysfunctions in AD and their impact on cellular physiology remains unknown. Here, we used plexDIA, an approach that parallelizes the acquisition of samples and peptides, to characterize proteomic changes in AD. Using human dorsolateral prefrontal cortex tissue, we identified 281 differentially abundant proteins in AD. By systematically analyzing cellular compartment-specific shifts in protein abundance, we identified an AD-specific decrease in levels of the 20S proteasome, the catalytic core of the cell’s primary protein degradation pathway. This alteration was accompanied by widespread decreases in proteasome subunit stoichiometries. Many proteasome substrate proteins were negatively correlated with 20S levels and increased in AD, suggesting that reduced 20S levels leads to abnormal protein accumulation. By analyzing proteins increased in AD, we identify key properties of such proteins. Namely, they have highly specific subcellular localizations and fast degradation rates, they contain signal sequences that allow them to be targeted for proteasomal degradation, and they are targeted by quality control pathways that recognize mislocalized proteins. Furthermore, we identify coherent sets of ubiquitin system enzymes, proteins that target substrates for proteasomal degradation, whose levels robustly discriminate AD from non-AD samples. One subset exhibited consistent increases in AD, while another exhibited consistent decreases, revealing complex alterations to the ubiquitin system in AD. Taken together, our results suggest that decreased ubiquitin-proteasome system capacity and impaired clearance of short-lived and mislocalized proteins contribute substantially to proteopathic burden in AD.
Preprint Ubiquitin-Proteasome System Alzheimer's Disease Protein Abundance