Biology subjects

Bennett, D. A.

Publications and source records attributed to Bennett, D. A..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics

Amyloid-beta (A{beta}) plaques and surrounding glial activation are prominent histopathological hallmarks of Alzheimers Disease (AD). However, it is unclear how A{beta} plaques interact with surrounding glial cells in the human brain. Here, we applied spatial transcriptomics (ST) and immunohistochemistry (IHC) for A{beta}, GFAP, and IBA1 to acquire data from 258,987 ST spots within 78 postmortem brain sections of 21 individuals. By coupling ST and adjacent-section IHC, we showed that low A{beta} spots exhibit transcriptomic profiles indicative of greater neuronal loss than high A{beta} spots, and high-glia spots present transcriptomic changes indicative of more significant inflammation and neurodegeneration. Furthermore, we observed that this ST glial response bears signatures of reported mouse gene modules of plaque-induced genes (PIG), oligodendrocyte (OLIG) response, disease-associated microglia (DAM), and disease-associated astrocytes (DAA), as well as different microglia (MG) states identified in human AD brains, indicating that multiple glial cell states arise around plaques and contribute to local immune response. We then validated the observed effects of A{beta} on cell apoptosis and plaque-surrounding glia on inflammation and synaptic loss using IHC. In addition, transcriptomic changes of iPSC-derived microglia-like cells upon short-interval A{beta} treatment mimic the ST glial response and mirror the reported activated MG states. Our results demonstrate an exacerbation of synaptic and neuronal loss in low-A{beta} or high-glia areas, indicating that microglia response to A{beta}-oligomers likely initiates glial activation in plaque-glia niches. Our study lays the groundwork for future pathology genomics studies, opening the door for investigating pathological heterogeneity and causal effects in neurodegenerative diseases.

genomics↗

bioRxiv2024

Contributions of genetic variation in astrocytes to cell and molecular mechanisms of risk and resilience to late onset Alzheimer's disease

Reactive astrocytes are associated with Alzheimers disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill-defined. Here we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from forty-four individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag-mass spectrometry. We demonstrate the utility of this resource in examining gene- and pathway-level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC-astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC-derived astrocytes from AD individuals are concordantly dysregulated in AD brain tissue. This includes increased prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components and reduced proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC-derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins. This study establishes an experimental system that integrates genetic information with a heterogeneous set of iPSCs to identify genetic contributions to molecular pathways affecting AD risk and resilience.

neuroscience↗

bioRxiv2024

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimers disease

Rates of cognitive decline in Alzheimers disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (A{beta}) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of A{beta} and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:A{beta}42, 10% beyond tau PET, and 50% beyond CSF NfL in A{beta} positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate in APOE4 carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25th percentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2- individuals (bottom 25th percentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by A{beta} and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of A{beta}, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

neuroscience↗

bioRxiv2024

Large- Scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity

AbstractO_ST_ABSIntroductionC_ST_ABSAlzheimers disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. MethodsDorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). ResultsAs a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. DiscussionThis comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

neuroscience↗

bioRxiv2024

Association of 10 VEGF Family Genes with Alzheimer's Disease Pathology at Single Cell Resolution

The cell-type specific role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimers disease (AD) is not well characterized. In this study, we utilized a single-nucleus RNA sequencing dataset from Dorsolateral Prefrontal Cortex (DLFPC) of 424 donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP) to investigate the effect of 10 VEGF genes (VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1, and NRP2) on AD endophenotypes. Mean age of death was 89 years, among which 68% were females, and 52% has AD dementia. Negative binomial mixed models were used for differential expression analysis and for association analysis with {beta}-amyloid load, PHF tau tangle density, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated signaling was profiled using CellChat. We discovered prefrontal cortical FLT1 expression was upregulated in AD brains in both endothelial and microglial cells. Higher FLT1 expression was also associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and {beta}-amyloid load. Similarly, higher endothelial FLT4 expression was associated with more {beta}-amyloid load. In contrast to the receptors, VEGFB showed opposing effects on {beta}-amyloid load whereby higher levels in oligodendrocytes was associated with high amyloid burden, while higher levels in inhibitory neurons was associated with lower amyloid burden. Finally, AD cells showed significant reduction in overall VEGF signaling comparing to those from cognitive normal participants. Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.

neuroscience↗

bioRxiv2024

Human brain aging heterogeneity observed from multi-region omics data reveals a subtype closely related to Alzheimer's disease

INTRODUCTION: The interconnection between brain aging and Alzheimers disease (AD) remain to be elucidated. METHODS: We investigated multi-omics (transcriptomics and proteomics) data from multiple brain regions (i.e., the hippocampus (HIPP), prefrontal cortex (PFC), and cerebellum (CRBL)) in cognitively normal individuals. RESULTS: We found that brain samples could be divided into ADL (AD-like) and NL (normal) subtypes which were correlated across brain regions. The differentially expressed genes in the ADL samples highly overlapped with AD gene signatures and the changes were consistent across brain regions (PFC and HIPP) in the multi-omics data. Intriguingly, the ADL subtype in PFC showed more differentially expressed genes than other brain regions, which could be explained by the baseline gene expression differences in the PFC NL samples. DISCUSSION: We conclude that brain aging heterogeneity widely exists, and our findings corroborate with the hypothesis that AD-related changes occur decades before the clinical manifestation of cognitive impairment in a sub-population.

neuroscience↗

bioRxiv2024

Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer's disease mouse model.

Characteristic cerebral pathological changes of Alzheimers disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as A{beta} peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation. We demonstrated previously that RHBLD4 cleaves APP in HEK293T cells, leading to decreased total APP and A{beta}. More recently, we showed that RHBDL4 processes APP in mouse primary mixed cortical cultures as well. Here, we aim to examine the physiological relevance of RHBDL4 in the brain. We first found that brain samples from AD patients and an AD mouse model (APPtg) showed increased RHBDL4 mRNA and protein expression. To determine the effects of RHBDL4s absence on APP physiology in vivo, we crossed APPtg mice to a RHBDL4 knockout (R4-/-) model. RHBDL4 deficiency in APPtg mice led to increased total cerebral APP and amyloidogenic processing when compared to APPtg controls. Contrary to expectations, as assessed by cognitive tests, RHBDL4 absence rescued cognition in 5-month-old female APPtg mice. Informed by unbiased RNAseq data, we demonstrated in vitro and in vivo that RHBDL4 absence leads to greater levels of active {beta}-catenin due to decreased proteasomal clearance. Decreased {beta}-catenin activity is known to underlie cognitive defects in APPtg mice and AD. Our work suggests that RHBDL4s increased expression in AD, in addition to regulating APP levels, leads to aberrant degradation of {beta}-catenin, contributing to cognitive impairment.

animal behavior and cognition↗

bioRxiv2024

Network Proteomics of the Lewy Body Dementia Brain Reveals Presynaptic Signatures Distinct from Alzheimer's Disease

Lewy body dementia (LBD), a class of disorders comprising Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimers disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinsons disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or "modules" of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.

systems biology↗

bioRxiv2024

Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the of AD-BXD Mouse Population

Alzheimers disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of- onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity of human populations, we utilized the AD-BXD mouse panel. This genetically diverse resource combines AD genotypes with multiple BXD strains to discover new genetic drivers of AD resilience. Comparing AD-BXD carriers to noncarrier littermates, we computed a novel quantitative metric for resilience to cognitive decline in the AD-BXDs. Our quantitative AD resilience trait was heritable and genetic mapping identified a locus on chr8 associated with resilience to AD mutations that resulted in amyloid brain pathology. Using a hippocampus proteomics dataset, we nominated the mitochondrial glutathione S reductase protein (GR or GSHR) as a resilience factor, finding that the DBA/2J genotype was associated with substantially higher GR abundance. By mapping protein QTLs (pQTLs), we identified synaptic organization and mitochondrial proteins coregulated in trans with a cis-pQTL for GR. We found four coexpression modules correlated with the quantitative resilience score in aged 5XFAD mice using paracliques, which were related to cell structure, protein folding, and postsynaptic densities. Finally, we found significant positive associations between human GSR transcript abundance in the brain and better outcomes on AD-related cognitive and pathology traits in the Religious Orders Study/Memory and Aging project (ROSMAP). Taken together, these data support a framework for resilience in which neuronal antioxidant pathway activity provides for stability of synapses within the hippocampus.

neuroscience↗

bioRxiv2024

Somatic cancer driver mutations are enriched and associated with inflammatory states in Alzheimer's disease microglia

Alzheimers disease (AD) is an age-associated neurodegenerative disorder characterized by progressive neuronal loss and pathological accumulation of the misfolded proteins amyloid-{beta} and tau1,2. Neuroinflammation mediated by microglia and brain-resident macrophages plays a crucial role in AD pathogenesis1-5, though the mechanisms by which age, genes, and other risk factors interact remain largely unknown. Somatic mutations accumulate with age and lead to clonal expansion of many cell types, contributing to cancer and many non-cancer diseases6,7. Here we studied somatic mutation in normal aged and AD brains by three orthogonal methods and in three independent AD cohorts. Analysis of bulk RNA sequencing data from 866 samples from different brain regions revealed significantly higher ([~]two-fold) overall burdens of somatic single-nucleotide variants (sSNVs) in AD brains compared to age-matched controls. Molecular-barcoded deep (>1000X) gene panel sequencing of 311 prefrontal cortex samples showed enrichment of sSNVs and somatic insertions and deletions (sIndels) in cancer driver genes in AD brain compared to control, with recurrent, and often multiple, mutations in genes implicated in clonal hematopoiesis (CH)8,9. Pathogenic sSNVs were enriched in CSF1R+ microglia of AD brains, and the high proportion of microglia (up to 40%) carrying some sSNVs in cancer driver genes suggests mutation-driven microglial clonal expansion (MiCE). Analysis of single-nucleus RNA sequencing (snRNAseq) from temporal neocortex of 62 additional AD cases and controls exhibited nominally increased mosaic chromosomal alterations (mCAs) associated with CH10,11. Microglia carrying mCA showed upregulated pro-inflammatory genes, resembling the transcriptomic features of disease-associated microglia (DAM) in AD. Our results suggest that somatic driver mutations in microglia are common with normal aging but further enriched in AD brain, driving MiCE with inflammatory and DAM signatures. Our findings provide the first insights into microglial clonal dynamics in AD and identify potential new approaches to AD diagnosis and therapy.

genomics↗

bioRxiv2023

Human disease-specific cell signatures in non-lesional tissue in Multiple Sclerosis detected by single-cell and spatial transcriptomics

Recent investigations of cell type changes in Multiple Sclerosis (MS) using single-cell profiling methods have focused on active lesional and peri-lesional brain tissue, and have implicated a number of peripheral and central nervous system cell types. However, an important question is the extent to which so-called "normal-appearing" non-lesional tissue in individuals with MS accumulate changes over the lifespan. Here, we compared post-mortem non-lesional brain tissue from donors with a pathological or clinical diagnosis of MS from the Religious Orders Study or Rush Memory and Aging Project (ROSMAP) cohorts to age- and sex-matched brains from persons without MS (controls). We profiled three brain regions using single-nucleus RNA-seq: dorsolateral prefrontal cortex (DLPFC), normal appearing white matter (NAWM) and the pulvinar in thalamus (PULV), from 15 control individuals, 8 individuals with MS, and 5 individuals with other detrimental pathologies accompanied by demyelination, resulting in a total of 78 samples. We identified region- and cell type-specific differences in non-lesional samples from individuals diagnosed with MS and/or exhibiting secondary demyelination with other neurological conditions, as compared to control donors. These differences included lower proportions of oligodendrocytes with expression of myelination related genes MOBP, MBP, PLP1, as well as higher proportions of CRYAB+ oligodendrocytes in all three brain regions. Among microglial signatures, we identified subgroups that were higher in both demyelination (TMEM163+/ERC2+), as well as those that were specifically higher in MS donors (HIF1A+/SPP1+) and specifically in donors with secondary demyelination (SOCS6+/MYO1E+), in both white and grey matter. To validate our findings, we generated Visium spatial transcriptomics data on matched tissue from 13 donors, and recapitulated our observations of gene expression differences in oligodendrocytes and microglia. Finally, we show that some of the differences observed between control and MS donors in NAWM mirror those previously reported between control WM and active lesions in MS donors. Overall, our investigation sheds additional light on cell type- and disease-specific differences present even in non-lesional white and grey matter tissue, highlighting widespread cellular signatures that may be associated with downstream pathological changes.

neuroscience↗

bioRxiv2023

Transcriptomic network analysis of brain and bone reveals shared molecular mechanisms underlyingAlzheimer's Disease and related dementias and Osteoporosis

Alzheimers disease and related dementias (ADRD) and Osteoporosis (OP) are two prevalent diseases of aging with numerous epidemiological associations, but the underlying molecular mechanisms contributing to this association are unknown. We used WGCNA (weighted gene co-expression network analysis) to develop transcriptomic networks in bone and brain tissue using two different studies to discover common molecular mechanisms. We used RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Memory and Aging Project), including a subset of 298 meeting criteria for inclusion in five ADRD categories and the full set in a secondary analysis, and RNA array data from transiliac bone in 84 participants from the Oslo study of postmenopausal women. After developing each network, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks, most notably among those modules linked to canonical Wnt signaling and skeletal tissue homeostasis and development. These results were preserved with a network from the full ROSMAP cohort (n=629), which included a broader spectrum of participants. Our results require validation in experimental studies but show support for Wnt signaling as an important driver of pathology in OP and ADRD. We additionally show a strong link between Dementia with Lewy bodies and bone outcomes. These results have translational significance in the development of novel treatments and biomarkers for both ADRD and OP.

neuroscience↗

bioRxiv2023

A public resource of single cell transcriptomes and multiscale networks from persons with and without Alzheimer's disease

The emergence of technologies that can support high-throughput profiling of single cell transcriptomes offers to revolutionize the study of brain tissue from persons with and without Alzheimers disease (AD). Integration of these data with additional complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link observed cell subpopulations and molecular network features within a broader disease-relevant context. We report here single nucleus RNA sequencing (snRNA-seq) profiles generated from superior frontal gyrus cortical tissue samples from 101 exceptionally well characterized, aged subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in peripheral hematological lab parameters, with these observations replicated in an independent, prospective cohort study of ageing and dementia. We also observed an AD-associated CD83(+) microglial subtype with unique molecular networks that encompass many known regulators of AD-relevant microglial biology, and which are associated with immunoglobulin IgG4 production in the transverse colon. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal novel disease biology. The transcriptomic, genetic, phenotypic, and network data resources described within this study are available for access and utilization by the scientific community.

genomics↗

bioRxiv2023

Psychosocial experiences are associated with human brain mitochondrial biology

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies heavily on energy transformation by mitochondria oxidative phosphorylation (OxPhos), and two main lines of evidence bi-directionally link mitochondria as both targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and possibly mood states alter multiple aspects of mitochondrial biology; and on the other hand, functional variations in mitochondrial OxPhos capacity alter social behavior, stress reactivity, and mood. However, knowledge on whether positive or negative psychosocial exposures and experiences are linked to mitochondrial biology in the human brain is currently unknown. By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we found that positive experiences (e.g. higher well-being) are linked to greater abundance of the mitochondrial OxPhos machinery, whereas negative experiences (e.g. higher negative mood) are linked to lower OxPhos protein content. Combined, psychosocial factors explained 18% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. To increase the sensitivity of our approach, we next interrogated mitochondrial psychobiological associations in specific neuronal and non-neuronal brain cells with single-nucleus RNA sequencing. These results revealed strong cell type specific associations, particularly between positive psychosocial experiences and molecular mitochondrial phenotypes in glial cells, whereas neurons tended to show opposite associations. Accordingly, in bulk transcriptomic analyses where all cells are pooled, these RNA-based associations were masked. Thus, our results highlight the likely underestimation of effect sizes in bulk brain tissues, and document novel cell type specific mitochondrial psychobiological associations in the human brain. Cell type specific mitochondrial recalibrations represent a potential psychobiological pathway linking positive and negative psychosocial experiences to human brain biology. Significance statementPsychosocial experiences predict health trajectories, but the underlying mechanism remains unclear. We found that positive psychosocial experiences are linked to greater abundance of the mitochondrial energy transformation machinery, whereas negative experiences are linked to lower abundance. Overall, we found that psychosocial experiences explain 18% of the variance in abundance of complex I proteins, the main entry point of the mitochondrial oxidative phosphorylation (OxPhos) system. At single-cell resolution using single nucleus transcriptomics, positive psychosocial experiences were particularly related to glial cell mitochondrial phenotypes. Opposite associations between glial cells and neurons were naturally masked in bulk transcriptomic analyses. Our results suggest that mitochondrial recalibrations in specific brain cell types may represent a potential psychobiological pathway linking psychosocial experiences to human brain health.

cell biology↗

bioRxiv2023

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments

Introductory paragraphOverexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klothos knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimers Disease (AD) and in corresponding human post-mortem brain tissue. To seek cell type distributions of the affected short RNAs, we isolated and FACS-sorted neurons and microglia from live human brain tissue, yielding detailed cell type-specific short RNA-seq datasets. Together, our findings revealed multiple Klotho deficiency-perturbed aging- and neurodegeneration-related long and short RNA transcripts in both neurons and glia from murine and human brain.

neuroscience↗

bioRxiv2023

Polygenic Risk Associated with Alzheimer's Disease and Other Traits Influences Genes Involved in T Cell Signaling and Activation

T cells, members of the adaptive immune system known for their ability to respond to an enormous variety of pathogens and other insults, are increasingly recognized as important mediators of pathology in neurodegeneration and other diseases. Previously, we and others have shown that T cell gene expression phenotypes are regulated by genetic variants associated with autoimmune disease, neurodegenerative disease, and inflammatory processes. However, many complex diseases have polygenic risk with thousands of common variants contributing a small amount to disease heritability. Here, we compute the polygenic risk score (PRS) of several autoimmune, neurological, and psychiatric disorders and present the first correlation of these PRSs with T cell gene expression, using transcriptomic and genomic sequencing data from a cohort of Alzheimers disease (AD) patients and age-matched controls. We validate our AD PRS against clinical metrics in our cohort and then compare PRS-associated genes across traits and four T cell subtypes. Several genes and biological pathways associated with the PRS for these traits relate to functions such as T cell chemotaxis, differentiation, response to and production of cytokines, and regulation of T cell receptor signaling. We also found that the trait-associated gene expression signature for certain traits was polarized towards a particular T cell subset, such as CD4+ for autoimmune disease traits or CD8+ for some psychiatric disease traits. Our findings may help guide efforts in precision medicine to target specific T cell functions in individuals with high polygenic risk for various complex diseases.

bioinformatics↗

bioRxiv2023

Interpretable deep learning approach for extracting cognitive features from hand-drawn images of intersecting pentagons in older adults

Hand drawing involves multiple neural systems for planning and precise control of sequential movements, making it a valuable cognitive test for older adults. However, conventional visual assessment of drawings may not capture intricate nuances that could help track cognitive states. To address this issue, we utilized a deep-learning model, PentaMind, to examine cognition-related features from hand-drawn images of intersecting pentagons. PentaMind, trained on 13,777 images from 3,111 participants in three aging cohorts, explained 23.3% of the variance in global cognitive scores, a comprehensive hour-long cognitive battery. The models performance, which was 1.92 times more accurate than conventional visual assessment, significantly improved the detection of cognitive decline. The improvement in accuracy was due to capturing additional drawing features that we found to be associated with motor impairments and cerebrovascular pathologies. By systematically modifying the input images, we discovered several important drawing attributes for cognition, including line waviness. Our results demonstrate that hand-drawn images can provide rich cognitive information, enabling rapid assessment of cognitive decline and suggesting potential clinical implications in dementia.

neuroscience↗

bioRxiv2023

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease

Alzheimers Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brains cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-{beta} proteinopathy while the other mediated the effect of amyloid-{beta} in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.

neuroscience↗