Biology subjects

Troncoso, J.

Publications and source records attributed to Troncoso, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Tauopathy primes co-filament assembly and dysfunction of TDP-43

While most Alzheimers disease (AD) which is associated with Limbic Predominant Age-related TDP-43 Encephalopathy (LATE) exhibits accelerated brain atrophy, the pathogenic mechanism remains elusive. We show here, in mice harboring depositions of amyloid-{beta} and tau, the age-dependent emergence of TDP-43 proteinopathy. We demonstrate that TDP-43 dysfunction facilitates caspase 3-mediated endoproteolysis of tau, accelerates tauopathy and exacerbates neuron loss. Unexpectedly, we found that the emergence and spread of TDP-43 proteinopathy is associated with the spread of tauopathy and correlated with co-filament assembly of tau and TDP-43. Importantly, TDP-43 dysfunction precedes such co-filament assembly and TDP-43 cytoplasmic aggregates. Consistent with the idea that tauopathy could prime co-filament assembly and proteinopathy of TDP-43 to exacerbate neurodegeneration, we found tau co-filament assembly with TDP-43 in AD and AD-LATE cases. These findings suggest that TDP-43 dysfunction accelerates tauopathy, which, in turn, primes co-filament assembly and dysfunction of TDP-43 to exacerbate neuron loss in AD-LATE, a pathogenic mechanism disclosing novel targets and therapeutic strategies.

neuroscience↗

bioRxiv2026

Reactive Astrocytes Drive Extracellular Acidification to Mediate α-Synuclein Neurodegeneration

Astrocytes are increasingly recognized as key players in neurodegeneration1-3, yet the molecular mechanisms by which they drive disease remain elusive. Here, we uncover a fundamental pathway in which reactive astrocytes fuel neurodegeneration in -synucleinopathies--including Dementia with Lewy bodies and Parkinsons disease dementia--by acidifying the brains extracellular environment. We demonstrate that both human patient tissue and a gut-to-brain -synuclein mouse model exhibit accumulation of reactive astrocytes and extracellular acidosis. Mechanistically, we show that astrocytic lysosomal exocytosis releases acidic contents, driving a drop in pH that activates neuronal acid-sensing ion channel 1a (ASIC1a), resulting in neuronal loss and behavioral decline. Blocking this pathway--either by inhibiting astrocytic lysosomal exocytosis or genetically or pharmacologically targeting neuronal ASIC1a--mitigates pathology and rescues neurodegenerative phenotypes in vivo. These findings provide a conceptual advance by establishing a mechanistic link between glial inflammation, acid-base homeostasis, and neuronal vulnerability, and suggest that targeting astrocyte-driven acidification or ASIC1a signaling could offer new avenues for disease modification in -synucleinopathies.

neuroscience↗

bioRxiv2025

Neuronal PARIS-STAT3 axis drives tau pathology and glial activation in Alzheimers disease

PARIS, a substrate of Parkin, accumulates in Parkinsons disease and promotes disease progression. Here, we demonstrate that PARIS also contributes to Alzheimers disease by elevating STAT3 transcriptional activity, thereby inducing tau pathology, hippocampal atrophy, and glial activation. Genetic depletion of Paris reduced tau phosphorylation and cognitive decline in tauopathy mice, whereas neuron-specific PARIS overexpression caused tau accumulation, gliosis, and memory impairment. In contrast, astrocyte-specific overexpression did not induce pathology, indicating that PARIS acts in neurons to drive tau phosphorylation and glial activation. The pathological features induced by neuronal PARIS overexpression were rescued by STAT3 inhibition, demonstrating that PARIS-STAT3 signaling underlies these effects. Moreover, Paris knockout did not alter pathology in the amyloid-driven mouse model, highlighting specificity for tau pathology. Together, these findings reveal PARIS as a neuronal regulator of STAT3 signaling that exacerbates tau-mediated neurodegeneration and identify the PARIS-STAT3 pathway as a potential therapeutic target in Alzheimers disease.

neuroscience↗

bioRxiv2025

Transcriptomic profiling of the middle temporal gyrus reveals differential glial/neuronal dysregulation across Alzheimer disease and aging.

Alzheimers disease (AD), the most common cause of dementia, is characterized by amyloid-{beta} plaques, neurofibrillary tangles, and widespread neuronal dysfunction. Aging, the strongest risk factor for AD, is also associated with some overlapping processes, such as neuronal cell transcriptional downregulation and glial cell activation. The middle temporal gyrus (MTG) is a brain region that supports semantic processing and default-mode connectivity and shows early vulnerability in both aging and AD. Here we profile bulk RNA-seq from 606 postmortem MTG samples with the goal of understanding the transcriptional changes associated with AD and aging. In 217 clinical and neuropathologically confirmed AD versus 290 no-dementia controls donors, we identify 613 differentially expressed genes (390 up, 223 down; |log2 fold change| [≥] 0.5; BH P < 0.05), with NPNT and ADAMTS2 among the top upregulated signals. Cell set enrichment indicates reduced excitatory neuronal signatures together with increased microglial, astrocytic, endothelial, and pericyte programs. Gene-set analyses reveal strong activation of angiogenesis, extracellular-matrix organization, wound response, adaptive immunity, and coordinated suppression of neuronal and mitochondrial processes, including synaptic signaling and respiratory-chain complexes. Multiscale coexpression mapping resolves three disease clusters: a neuron-mitochondrial module suppressed in AD (M5; hub PJA2; key driver GABRB3), a microglial immune module upregulated in AD (M6; hub C1QC; key driver FCER1G), and an increased astrocyte-vascular extracellular-matrix module in AD (M8; hub ESAM; key driver TAGLN). Across 324 non-AD controls aged 24-108 years, aging is associated with declines in gene expression associated with translation, proteostasis, and mitochondrial function and increases in those linked to oligodendrocyte and myelination programs (for example M4; hub CNTN2; key driver MOBP); in a 65+ subset, neuronal and protein-folding modules show the strongest decrements with reduced glial gene expression upregulatio. Our results indicate that late-life aging involves increased glial responses and neuronal/proteostasis suppression, whereas AD is also associated with immune- vascular-ECM activation and suppression of neuronal programs.

genomics↗

bioRxiv2025

Repeat associated non-AUG translation as a common mechanism for the polyGln ataxias

Determining if repeat associated non-AUG (RAN) proteins contribute to the CAG polyGln-encoding spinocerebellar ataxias (CAG-SCAs) is critical for understanding mechanisms and developing therapies for these diseases. Immunohistochemistry using antibodies against polySer and polyLeu repeats and locus specific C-terminal regions show sense polySer (AGC frame) and antisense polyLeu (CUG frame) RAN proteins accumulate in affected grey and white-matter brain regions, throughout the cerebellum and pons, in SCA1, SCA2, SCA3, SCA6, and SCA7 autopsy brains. Cerebellar white matter regions with prominent polySer and polyLeu but minimal polyGln aggregates show demyelination, white matter loss, and activated microglia. In SCA3 mice, RAN proteins accumulate in an age-dependent manner. In neural cells, polySer and polyLeu RAN proteins are toxic and cause autophagic dysfunction. In cells, the FDA-approved drug metformin decreases RAN protein levels and reduces toxicity. Taken together, these data identify sense and antisense RAN proteins as a common molecular mechanism shared by the CAG-SCAs.

neuroscience↗

bioRxiv2025

UNC-45A Drives ATP-Independent Microtubule Destabilization via Defect Recognition and Repair Inhibition Contributing to Neurite Dystrophy

UNC-45A is the only known ATP-independent microtubule severing protein. Using in vitro reconstitution and TIRF microscopy, we show that, unlike canonical severing enzymes such as katanin, spastin, and fidgetin, which hydrolyze ATP to remove tubulin dimers and promote lattice repair, UNC-45A selectively binds to pre-existing microtubule defects and inhibits GTP-tubulin incorporation. This mechanism prevents the formation of stabilized hot spots that typically protect microtubules from disassembly, resulting in persistent lattice damage and net microtubule loss, even in the presence of physiological levels of free GTP-tubulin. We further demonstrate that UNC-45A localizes near amyloid deposits in both mouse models and human cases of Alzheimers disease (AD). In cultured neurons, UNC-45A accumulates in axonal swellings--regions of pronounced microtubule disruption and experimental surrogates for dystrophic neurites in AD--and exacerbates their size and number, particularly under conditions mimicking microtubule damage. Notably, this is the first report of a microtubule severing protein that both localizes near amyloid plaques in tissue and accumulates in neurite swellings in cultured neurons, where it modulates their pathology. Together, our findings establish the mechanism of ATP-independent, damage-responsive severing pathway that couple defects recognition to repair inhibition, defining a new paradigm in microtubule quality control with broad implications for cytoskeletal integrity and remodeling in health and disease.

cell biology↗

bioRxiv2025

Tau-seed interactome analysis reveals distinct functional signatures in Alzheimer's disease across model systems.

Tau aggregates propagate through the brain in a prion-like manner in Alzheimers disease (AD) and other tauopathies, but the molecular identity and functional partners of the seeding-competent Tau species remain poorly defined. Here, we present an unbiased proteomic profiling of a high-molecular-weight (HMW) Tau-seed isolated from AD patient brains. We contrast this interactome with that of a biochemically similar, seeding-incompetent HMW-Tau species from age-matched healthy controls. Despite comprising less than 5% of total Tau in the brain, Tau-seed associates with a distinct set of proteins enriched in synaptic, mitochondrial, and vesicle-trafficking functions. Cross-species functional screening in Drosophila and mouse models identifies interactors that modulate Tau toxicity and seeding. Spatially resolved analysis of postmortem AD brains reveals heterogenous co-deposition of these proteins with Tau aggregates, suggesting functionally distinct Tau-seed complexes. Together, this dataset provides a framework for understanding selective Tau-seed toxicity and identifies candidate regulators of Tau propagation with therapeutic potential.

neuroscience↗

bioRxiv2025

DCPS modulates TDP-43 mediated neurodegeneration through P-body regulation

The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimers disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping enzyme scavenger (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation, via disrupting the properties and function of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Dissecting the molecular landscape of Parkinson's disease and Parkinson's disease dementia using highly efficient snRNA-seq (HIF-snRNA-seq)

This study presents a transcriptomic analysis of the cingulate cortex (CING) in Parkinsons disease (PD) and Parkinsons disease dementia (PDD) using a High-efficiency single-nucleus RNA sequencing (HiF-snRNA-seq) protocol optimized for post-mortem brain samples. RNA quality prediction, poly-A tailing, and dCas9-targeted depletion enabled analysis of 77 high-quality samples from 240 cases, yielding over 2 million nuclei classified into seven major cell types. Disease conditions revealed altered astrocyte and microglia proportions, implicating their roles in neuroinflammation. Differential expression analysis identified unique and shared genes across PD and PDD, linked to synaptic remodeling, stress responses, and inflammation. Stage-specific analysis uncovered tau-dependent early-stage genes and inflammation-associated late-stage genes. This study highlights the CINGs central role in PD and PDD pathophysiology, offering insights into disease mechanisms and identifying candidate genes and pathways for therapeutic and biomarker development.

genomics↗

bioRxiv2024

Resiliency to Alzheimer's disease neuropathology can be distinguished from dementia using cortical astrogliosis imaging

Despite the presence of significant Alzheimers disease (AD) pathology, characterized by amyloid {beta} (A{beta}) plaques and phosphorylated tau (pTau) tangles, some cognitively normal elderly individuals do not inevitably develop dementia. These findings give rise to the notion of cognitive resilience, suggesting maintained cognitive function despite the presence of AD neuropathology, highlighting the influence of factors beyond classical pathology. Cortical astroglial inflammation, a ubiquitous feature of symptomatic AD, shows a strong correlation with cognitive impairment severity, potentially contributing to the diversity of clinical presentations. However, noninvasively imaging neuroinflammation, particularly astrogliosis, using MRI remains a significant challenge. Here we sought to address this challenge and to leverage multidimensional (MD) MRI, a powerful approach that combines relaxation with diffusion MR contrasts, to map cortical astrogliosis in the human brain by accessing sub-voxel information. Our goal was to test whether MD-MRI can map astroglial pathology in the cerebral cortex, and if so, whether it can distinguish cognitive resiliency from dementia in the presence of hallmark AD neuropathological changes. We adopted a multimodal approach by integrating histological and MRI analyses using human postmortem brain samples. Ex vivo cerebral cortical tissue specimens derived from three groups comprised of non-demented individuals with significant AD pathology postmortem, individuals with both AD pathology and dementia, and non-demented individuals with minimal AD pathology postmortem as controls, underwent MRI at 7 T. We acquired and processed MD-MRI, diffusion tensor, and quantitative T1 and T2 MRI data, followed by histopathological processing on slices from the same tissue. By carefully co-registering MRI and microscopy data, we performed quantitative multimodal analyses, leveraging targeted immunostaining to assess MD-MRI sensitivity and specificity towards A{beta}, pTau, and glial fibrillary acidic protein (GFAP), a marker for astrogliosis. Our findings reveal a distinct MD-MRI signature of cortical astrogliosis, enabling the creation of predictive maps for cognitive resilience amid AD neuropathological changes. Multiple linear regression linked histological values to MRI changes, revealing that the MD-MRI cortical astrogliosis biomarker was significantly associated with GFAP burden (standardized {beta}=0.658, pFDR<0.0001), but not with A{beta} (standardized {beta}=0.009, pFDR=0.913) or pTau (standardized {beta}=-0.196, pFDR=0.051). Conversely, none of the conventional MRI parameters showed significant associations with GFAP burden in the cortex. While the extent to which pathological glial activation contributes to neuronal damage and cognitive impairment in AD is uncertain, developing a noninvasive imaging method to see its affects holds promise from a mechanistic perspective and as a potential predictor of cognitive outcomes.

neuroscience↗

bioRxiv2023

An autophagy adaptor TRIAD3A promotes tau fibrillation by phase separation

Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report an RBR-type E3 ligase TRIAD3A functions as a novel autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing ageprogressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyzes a novel mixed K11/K63 polyubiquitin chain and self assembles into liquid-liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and via LC3 interacting regions targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to amyloid aggregates without the transitional liquid phase of tau. In vivo studies reveal TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis, and increases pathological tau spreading. In human Alzheimers disease brain, TRIAD3A colocalizes with tau amyloid in multiple histological forms suggesting a role in tau homeostasis. TRIAD3A is the first autophagic adaptor that utilizes E3-ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Pathological Tau transmission initiated by binding lymphocyte-activation gene 3

The spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimers disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity1, 2. Clinical observation combined with complementary experimental studies3, 4 have shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remains poorly understood. Here, we show that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF, but not monomer, of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. Our results identify neuronal Lag3 as a receptor of pathologic Tau in the brain, and for AD and related Tauopathies a therapeutic target. One Sentence SummaryLag3 is a neuronal receptor specific for Tau PFF, and is required for uptake, propagation and transmission of Tau pathology.

neuroscience↗

bioRxiv2023

Thioflavin T In-gel Stain to Study Protein Misfolding in Frozen Tissue Specimens

There are limited options to quantify and characterize amyloid species from biological samples in a simple fashion. Thioflavin T (ThT) has now been used for decades to stain amyloid fibrils but to our knowledge we were the first to use it in-gel. Thioflavin T in-gel stain is convenient as it is fast, inexpensive, available to most labs, compatible with other fluorescent stains and downstream analyses such as mass spectrometry (MS).

biochemistry↗

bioRxiv2022

Enhanced mTORC1 signaling and Protein Synthesis in Parkinson Disease Pathogenesis

Pathologic -syn destabilizes the TSC 1 and 2 complex leading to mTORC1 activation, enhanced protein translation and neurodegeneration in PD. AbstractPathological -synuclein (-syn) plays an important role in the pathogenesis of -synucleinopathies such as Parkinsons disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic -syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the -syn preformed fibril (PFF) and Drosophila -syn transgenic models of pathologic -syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic -syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD.

neuroscience↗

bioRxiv2022

Transcriptome landscape of kleptoplastic sea slug Elysia viridis

Certain sacoglossan sea slugs can sequester and maintain photosynthetically active chloroplasts through algae feeding, a phenomenon called kleptoplasty. The period while these plastids remain active inside the slugs body is species- and environment-dependent and can span from a few days to more than three weeks. Here we report for the first time the transcriptome of sea slug Elysia viridis (Montagu, 1804), which can maintain kleptoplasts for more than two weeks and is distributed along all the Atlantic European coastline. The obtained transcriptome of E. viridis comprised 12,884 protein-coding sequences (CDS). The shortest one was 261bp, and the longest 8,766bp; the whole transcriptome has a total length of 9.3Mb (Table S4 and Fig. S2). Analysing these CDS, we identified 9,422 different proteins, with best hits mainly from two genera: Elysia (87.2%), and Plakobranchus (11.0%) (Fig. S2); the other 2.3% corresponded to multiple genera of sea slugs and snails (Tectipleura) (Kano et al., 2016). We got the functional annotation (Gene Ontologies, GO) corresponding to 9,333 CDS: 4,755 CDS associated with 2,583 Biological Process (BP); 5,466 CDS linked to 683 Cellular Components (CC); and 6,693 related to 1,606 Molecular Functions (MF). We identified 201 CDS related to response to stress (GO:0006950) and 10 CDS associated with the regulation of response to stress (GO:0080134). Focussing on the ROS-quenching toolkit, we found 24 CDS related to oxidoreductase complex (GO:1990204) and 560 annotated with oxidoreductase activity (GO:0016491) acting in a large number of donors, e.g., CH-OH, CH=O, C=O, CH and CH2. In addition, we found 39 CDS with antioxidant activity (GO:00162099) and other CDS with ROS-quenching function: superoxide dismutase (GO:0004784), peroxidase (GO:0004601), glutathione oxidoreductase (GO:0097573) and peroxidase (GO:0004602); and thioredoxin peroxidase (GO:0008379) activity. Furthermore, we found 8 CDS related to the symbiont response (GO:0140546) and nine related to the pattern recognition receptor signalling pathway (GO:0002221).

evolutionary biology↗

bioRxiv2022

Amygdalar and ERC Rostral Atrophy and Tau Pathology Reconstruction in Preclinical Alzheimer's Disease

Previous research has emphasized the unique impact of Alzheimers Disease (AD) pathology on the medial temporal lobe (MTL), a reflection that tau pathology is particularly striking in the entorhinal and transentorhinal cortex (ERC, TEC) early in the course of disease. However, other brain regions are affected by AD pathology during its early phases. Here, we use longitudinal diffeomorphometry to measure the atrophy rate from MRI of the amygdala compared with that in the ERC and TEC in controls, individuals who progressed from normal cognition to mild cognitive impairment (MCI), and individuals with MCI who progressed to AD dementia, using a dataset from the Alzheimers Disease Neuroimaging Initiative (ADNI). Our results show significantly higher atrophy rates of the amygdala in both preclinical and MCI converters compared to controls, with rates of volume loss comparable to rates of thickness loss in the ERC and TEC. Using our recently developed method, referred to as Projective LDDMM, we map measures of neurofibrillary tau tangles (NFTs) from digital pathology to MRI atlases and reconstruct, for the first time, dense 3D spatial distributions of NFT density within regions of the MTL. The distribution of NFTs is consistent with the MR atrophy rates, revealing high densities not only in ERC, but in the amygdala and rostral third of the MTL. The similarity of the location of NFTs and shape changes in a well-defined clinical population suggests that amygdalar atrophy rate, as measured through MRI may be a viable biomarker for AD. PACS0000, 1111 2000 MSC0000, 1111 HighlightsO_LIAmygdala atrophy rate estimated from MRIs in preclinical Alzheimers disease (AD) C_LIO_LI3D distributions of neurofibrillary tau tangles (NFTs) reconstructed from 2D histology C_LIO_LINFTs highest in the rostral medial temporal lobe, including amygdala and ERC C_LIO_LIAmygdala atrophy rate is comparable to ERC atrophy rate in preclinical AD C_LIO_LIAmygdala and ERC atrophy rates as potential biomarkers rooted in NFT pathology C_LI

bioengineering↗

bioRxiv2022

Projective LDDMM: Spatially Reconstructing a Story of Rostrally-Dominant Tau in Alzheimer's Disease

Since Braaks initial histological observations, it has been recognized that Alzheimers disease (AD) neurofibrillary tangles (NFTs) appear in the medial temporal lobe (MTL) of the brain very early in the disease course. MRI-based shape diffeomorphometry markers have demonstrated pre-clinical AD changes in the MTL but it has not been possible to confirm that these MRI changes correspond to the presence of NFTs. Here, we present a method termed Projective LDDMM for aligning sparse measurement profiles of AD pathology (i.e., 2D digital histology images) with 3D MRI. We reconstruct measures of 2D NFT density in the dense metric of 3D MRI, using the Mai Paxinos Atlas coordinates for two cases of advanced AD. Analyses reveal the highest levels of NFT density in the rostral third (10-15 mm) of the hippocampus and the adjoining regions of the entorhinal cortex and amygdala. These findings emphasize the selective vulnerability of MTL subregions in AD, and suggest that high resolution MRI methods might benefit from focusing on the rostral MTL to more closely link these MRI images to AD neuropathology.

bioengineering↗

bioRxiv2019

Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. However, little is known about its molecular effects on the human brain and how these alterations may contribute to dementia. Here, we investigated these questions using large-scale quantification of over 8300 proteins from 438 post-mortem brains from a discovery and replication cohort. A proteome-wide association study and protein network analysis of cerebral atherosclerosis found 114 proteins and 5 protein co-expression modules associated with cerebral atherosclerosis. Enrichment analysis of these proteins and modules revealed that cerebral atherosclerosis was associated with reductions in synaptic signaling and RNA splicing and increases in oligodendrocyte development and myelination. A subset of these proteins (n=23) and protein modules (n=2) were also associated with Alzheimers disease (AD) dementia, implicating a shared mechanism with AD through decreased synaptic signaling and regulation and increased myelination. Notably, neurofilament light (NEFL) and medium (NEFM) chain proteins were among these 23 proteins, and our data suggest they contribute to AD dementia through cerebral atherosclerosis. Together, our findings offer insights into effects of cerebral atherosclerosis on the human brain proteome, and how cerebral atherosclerosis contributes to dementia risk.

neuroscience↗