Biology subjects

Taga, M.

Publications and source records attributed to Taga, M..

At least 19 recordsLinked to original sources

bioRxiv2026

High-Dimensional Multi-omic Mapping of Post-Mortem Human Brain Using Iterative Indirect Immunofluorescence Imaging on Xenium-Processed Tissues

Spatial transcriptomics approaches provide crucial insights into gene expression distribution within intact tissue architecture, but they encounter limitations in detecting morphologically complex cell types, assessing their spatial associations with pathology, and accurately annotating cell types using RNA data alone. Therefore, we developed a robust post-processing workflow integrating Xenium spatial technology with iterative indirect immunofluorescence imaging (4i) on formalin-fixed paraffin-embedded (FFPE) human brain tissue. The post-Xenium 4i protocol presented here allows multi-omic tissue mapping, enabling deeper investigation of pathological microenvironments defined by the spatial distribution of neuropathological hallmarks and enrichment of specific cell populations. We applied this workflow on calcarine cortex tissue sections where cerebral amyloid angiopathy (CAA) burden is present, in addition to amyloid plaques and tau pathology, generating a 15-plex image that captures the complexity of the pathological microenvironment.

neuroscience↗

bioRxiv2025

Mapping disease critical spatially variable gene programs by integrating spatial transcriptomics with human genetics

Spatial gene expression patterns underlie tissue organization, development, and disease, yet current methods for detecting spatially variable genes (SVGs) lack the flexibility to capture multi-scale structure, ensure robustness across platforms, and integrate with genetic data to assess disease relevance. We present Spacelink, a unified framework that models spatial variability of a gene at both whole-tissue and cell-type resolution using an adaptive mixture of data-driven spatial kernels and summarizes it using an Effective Spatial Variability (ESV) metric. Spacelink achieved up to 3.2x higher detection power over eight existing global SVG and cell-type SVG methods while showing consistently superior FDR control across 34 different simulation settings and also showed superior cross-platform concordance in matched tissue Visium and CosMx datasets. Applied to 3 healthy CosMx human tissues (brain cortex, lymph node, liver), Spacelink revealed that SVGs are highly informative for 113 complex traits and diseases (average GWAS sample size = 340,406). Spacelink showed up to 2.2x higher disease informativeness over competing methods in tissue-relevant complex diseases and traits, conditional on putative non-spatial expression-level confounders. Applied to a mouse organogenesis Stereo-seq atlas (8 developmental stages), Spacelink identified 145 genes with stage-associated ESV within brain independent of mean expression, that are enriched in pathways like Wnt signaling and Rap1 signaling characterizing early and late development, respectively. Integration with in vivo Perturb-seq targeting 35 de novo ASD risk genes revealed that perturbations in excitatory neurons and astrocytes preferentially altered spatially structured downstream gene programs (1.7-2.2x higher average ESV across stages than other cell types), many of which were enriched for polygenic autism GWAS loci. In neurodegeneration, analysis of 32 Visium dorsolateral prefrontal cortex samples spanning Alzheimers disease (AD) pathology stages identified 334 genes with decreasing ESV along amyloid burden (enriched for glycolysis) and 216 genes with decreasing ESV along tau tangle accumulation (enriched for apoptotic pathways). Several AD risk genes (PKM, CLU, GPI) showed conserved reductions in spatial variability with AD pathology in both human and 5xFAD mouse, with PKM linking to a colocalized splicing QTL and amyloid burden QTL variant. These results highlight the utility of Spacelink in decoding spatially variable gene programs that connect tissue architecture to disease genetics.

genomics↗

bioRxiv2025

Automated image segmentation uncovers the role of CD74high human microglia in cognitive decline

The role of activated microglia in Alzheimers disease (AD) is well established; the proportion of stage III activated microglia has been associated with AD and cognitive decline, but this morphologically defined subtype is relatively uncommon (1-2% of microglia) and its cellular function is unknown. Single-cell RNA-sequencing revealed CD74 as a marker gene that is enriched in immunologically active microglial subtypes associated with AD. Here, we evaluated the relationship between CD74 expression, AD- related traits, and microglial morphology using dorsolateral prefrontal cortex samples from two brain collections (ROSMAP: n=63, NYBB: n=91). An image segmentation pipeline using CellProfiler was developed to extract features from entire tissue sections. The pipeline automatically delineated gray and white matter regions and segmented 1,120,780 gray matter microglia. In a meta-analysis of the two datasets, we find an increase in frequency of microglia with high CD74 expression (CD74high) in relation to AD dementia (p = 0.038), particularly in the phase of terminal, accelerated cognitive decline before death. These microglia have a more rounded, amoeboid shape (ROSMAP: p = 1.4x10-6; NYBB: p = 2x10-13) which is a characteristic morphology of activated stage III microglia. Results were consistent across both datasets, highlighting the robustness of our cellular segmentation approach. This study identifies a potential role for CD74high microglia and the CD74 ligand MIF in cognitive decline, and it provides evidence for a partially overlapping but distinct role for CD74high microglia and morphologically defined stage III microglia, whose functional properties have remained poorly understood. These CD74high microglia appear to be enriched for genes involved in cytokine response for class I and II antigen presentation, as well as regulation of T cell proliferation. These findings begin to link microglial subtypes defined by single-cell transcriptomic data with those characterized by classical morphological criteria to resolve the roles of different microglial functions to distinct stages in the trajectory to AD.

neuroscience↗

bioRxiv2025

CD33-CD45 Interaction Reveals a Mechanistic Link to Alzheimer's Disease Susceptibility

The innate immune gene CD33, encoding a myeloid inhibitory sialic acid-binding receptor, is associated with Alzheimers disease (AD) susceptibility. The AD-associated rs3865444CC risk variant reduces splicing of the sialic acid-binding domain and increases expression of the full-length (sialic acid-binding) CD33 isoform seven-fold compared to the rs3865444AA protective genotype. Here we identify CD45 as an immune cell-specific sialic acid-dependent cis CD33 binding partner, whose phosphatase activity is inhibited by CD33. Overexpression of CD33 or loss of CD45 contributes to impaired microglial clearance of amyloid beta and amyloid beta-induced loss of dendritic spines in microglial-neuronal co-cultures, aligning with a detrimental effect of CD33-mediated inhibition of CD45. CD33-CD45 interaction frequency was increased in monocytes from individuals with the rs3865444CC risk variant compared to rs3865444AA, as well as in AD compared to controls, independent of genotype. Furthermore, an interaction between CD33 and PTPRC (encoding CD45) gene expression in human brain tissue was associated with a pathological diagnosis of AD and global burden of AD pathology. Our findings thus establish a functional interaction between CD33 and CD45 relevant to AD susceptibility and systemic myeloid dysfunction in this disease.

neuroscience↗

bioRxiv2025

CD33 and Clusterin Interact Biophysically and Genetically to Modulate Alzheimer Risk

We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimers disease (AD). The full-length CD33M isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and A{beta}). This interaction induces CD33M inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques. Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches. Our work also highlights several other unexpected aspects of CD33 biology, including a soluble shed extracellular fragment of CD33M and a similar soluble secreted product arising from a truncating mutation in the CD33 extracellular domain (CD33M{Delta}4bp).

neuroscience↗

bioRxiv2025

A proteogenomic tool uncovers protein markers for human microglial states

Human microglial heterogeneity has been largely described using transcriptomic data. Here, we introduce a microglial proteomic data resource and a Cellular Indexing of Transcriptomes and Epitopes by Sequencing panel enhanced with antibodies targeting 17 microglial cell surface proteins (mCITE-Seq). We evaluated mCITE-Seq on HMC3 microglia-like cells, induced-pluripotent stem cell-derived microglia (iMG), and freshly isolated primary human microglia. We identified novel protein microglial markers such as CD51 and relate expression of 101 cell surface proteins to transcriptional programs. This results in the identification and validation of three protein marker combinations with which to purify microglia enriched with each of 23 transcriptional programs; for example, CD49D, HLA-DR and CD32 enrich for GPNMBhigh ("disease associated") microglia. Further, we identify and validate proteins - SIRPA, PDPN and CD162 - that differentiate microglia from infiltrating macrophages. The mCITE-Seq panel enables the transition from RNA-based classification and facilitates the functional characterization and harmonization of model systems.

neuroscience↗

bioRxiv2025

A factor-based analysis of individual human microglia uncovers regulators of an Alzheimer-related transcriptional signature

Human microglial heterogeneity is only beginning to be appreciated at the molecular level. Here, we present a large, single-cell atlas of expression signatures from 441,088 live microglia broadly sampled across a diverse set of brain regions and neurodegenerative and neuroinflammatory diseases obtained from 161 donors sampled at autopsy or during a neurosurgical procedure. Using single-cell hierarchical Poisson factorization (scHPF), we derived a 23-factor model for continuous gene expression signatures across microglia which capture specific biological processes (e.g., metabolism, phagocytosis, antigen presentation, inflammatory signaling, disease-associated states). Using external datasets, we evaluated the aspects of microglial phenotypes that are encapsulated in various in vitro and in vivo microglia models and identified and replicated the role of two factors in human postmortem tissue of Alzheimers disease (AD). Further, we derived a complex network of transcriptional regulators for all factors, including regulators of an AD-related factor enriched for the mouse disease-associated microglia 2 (DAM2) signature: ARID5B, CEBPA, MITF, and PPARG. We replicated the role of these four regulators in the AD-related factor and then designed a multiplexed MERFISH panel to assess our microglial factors using spatial transcriptomics. We find that, unlike cells with high expression of the interferon-response factor, cells with high expression of the AD DAM2-like factor are widely distributed in neocortical tissue. We thus propose a novel analytic framework that provides a taxonomic approach for microglia that is more biologically interpretable and use it to uncover new therapeutic targets for AD.

neuroscience↗

bioRxiv2024

Spatial Transcriptomic Analysis Identifies a SERPINA3-Expressing Astrocytic State Associated with the Human Neuritic Plaque Microenvironment

Single-nucleus transcriptomic studies have revealed glial cell states associated with Alzheimers disease; however, these nuclei are dissociated from the complex architecture of the human neocortex. Here, we successfully performed an unbiased distance-based analytic strategy on spatially-registered transcriptomic data. Leveraging immunohistochemistry in the same tissue section, our analyses prioritized SERPINA3 and other genes, such as metallothioneins, as altered in the vicinity of neuritic amyloid plaques. Results were validated at the protein level by immunofluorescence, highlighting that a reactive SERPINA3+ astrocyte subtype, Ast.5, plays a role in the plaque microenvironment.

neuroscience↗

bioRxiv2024

Corticospinal and corticoreticulospinal projections benefit motor behaviors in chronic stroke

After corticospinal tract (CST) stroke, several motor deficits in the upper extremity (UE) emerge, including diminished muscle strength, motor control, and muscle individuation. Both the ipsilesional CST and contralesional corticoreticulospinal tract (CReST) innervate the paretic UE and may have different innervation patterns for the proximal and distal UE segments. These patterns may underpin distinct pathway relationships to separable motor behaviors. In this cross-sectional study of 15 chronic stroke patients and 28 healthy subjects, we examined two key questions: (1) whether segmental motor behaviors differentially relate to ipsilesional CST and contralesional CReST projection strengths, and (2) whether motor behaviors segmentally differ in the paretic UE. We measured strength, motor control, and muscle individuation in a proximal (biceps, BIC) and distal muscle (first dorsal interosseous, FDI) of the paretic UE. We measured the projection strengths of the ipsilesional CST and contralesional CReST to these muscles using transcranial magnetic stimulation (TMS). Stroke subjects had abnormal motor control and muscle individuation despite strength comparable to healthy subjects. In stroke subjects, stronger ipsilesional CST projections were linked to superior motor control in both UE segments, whereas stronger contralesional CReST projections were linked to superior muscle strength and individuation in both UE segments. Notably, both pathways also shared associations with behaviors in the proximal segment. Motor control deficits were segmentally comparable, but muscle individuation was worse for distal motor performance. These results suggest that each pathway has specialized contributions to chronic motor behaviors but also work together, with varying levels of success in supporting chronic deficits. Key points summaryO_LIIndividuals with chronic stroke typically have deficits in strength, motor control, and muscle individuation in their paretic upper extremity (UE). It remains unclear how these altered behaviors relate to descending motor pathways and whether they differ by proximal and distal UE segment. C_LIO_LIIn this study, we used transcranial magnetic stimulation (TMS) to examine projection strengths of the ipsilesional corticospinal tract (CST) and contralesional corticoreticulospinal tract (CReST) with respect to quantitated motor behaviors in chronic stroke. C_LIO_LIWe found that stronger ipsilesional CST projections were associated with better motor control in both UE segments, whereas stronger contralesional CReST projections were associated with better strength and individuation in both UE segments. In addition, projections of both pathways shared associations with motor behaviors in the proximal UE segment. C_LIO_LIWe also found that deficits in strength and motor control were comparable across UE segments, but muscle individuation was worse with controlled movement in the distal UE segment. C_LIO_LIThese results suggest that the CST and CReST have specialized contributions to chronic motor behaviors and also work together, although with different degrees of efficacy. C_LI

neuroscience↗

bioRxiv2024

Phosphodiesterase-5 inhibition inhibits epithelial ATP release and restores detrusor contractility in rats with type 2 diabetes via an increase in bladder blood flow

PurposeThe bladder dysfunction associated with type 2 diabetes mellitus (T2DM) involves urine storage and voiding disorders. We evaluated the pathologic conditions of bladder wall in a rat model of T2DM and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil (TA). Materials and MethodsMale Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats comprised T2DM and control groups. TA was orally administered for 12 weeks. The bladder blood flow and ATP released from the bladder epithelium were measured using laser speckle imaging and an organ bath bladder distention test. The expression levels of markers of hypoxia, pro-inflammatory cytokines, and growth factors in the bladder wall were measured by real-time PCR and ELISA. The contractions of bladder strips in response to KCl and carbachol were monitored in OLETF rats. ResultsThe bladder blood flow was impaired and there was greater ATP release and vesicular nucleotide transporter (VNUT) expression in the OLETF rats than in the LETO rats, but these effects were suppressed by TA administration. Furthermore, the high expression of HIF-1, 8-OHdG, IL-6, TNF-, IGF-1, and bFGF in the OLETF rats was reduced by TA administration. In the OLETF rats, the contractile responses of bladder strips to KCl and carbachol were impaired, but were restored by TA administration. ConclusionsThe impairment of bladder blood flow in rats with T2DM is associated with greater ATP release and the upregulation of VNUT, markers of hypoxia, proinflammatory cytokines, and growth factors in the bladder epithelium. PDE5 inhibition has the potential to prevent the storage and voiding dysfunction associated with T2DM.

pharmacology and toxicology↗

bioRxiv2024

An image segmentation pipeline optimized for human microglia uncovers sources of morphological diversity in Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the accumulation of beta-amyloid plaques and neurofibrillary tangles. Microglia, the resident immune cells in the brain, play a crucial role in AD pathology, particularly in relation to amyloid plaques. However, the exact role of plaque-associated microglia and their morphological changes in AD progression remains under debate. In this study, we aimed to establish an automated image segmentation and analysis pipeline optimized for the detection of human microglia, and we assessed its utility by systematically investigating topological relationships between microglia morphology and amyloid plaques. We accessed post-mortem brain tissue samples from persons with AD and utilized immunofluorescence staining to label microglia (IBA1) and amyloid plaques (A{beta}1-42). The acquired images were processed using CellProfiler, an open-source image analysis software, to automatically segment microglia and measure their morphological features. Specifically, since activated (stage III) microglia have a condensed morphology with retracted processes, we prioritized a morphological parameter called "compactness" in our analyses to capture shape changes in microglial found in proximity to amyloid plaques. Our results revealed that microglia unassociated with plaques (Mip-) were more abundant than microglia associated with plaques (Mip+) in the Dorsolateral Prefrontal Cortex (DLPFC) of both men and women with AD. Furthermore, we observed that Mip+ exhibited a significantly more ramified shape and had a higher expression of the IBA1 microglial marker gene compared to Mip. There were no significant differences in microglia morphology between men and women. Our study highlights the utility of automated image analysis in characterizing detailed microglia morphology at the single-cell level and its relationship with AD pathology.

pathology↗

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

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↗

bioRxiv2022

A cross-disease human microglial framework identifies disease-enriched subsets and tool compounds for microglial polarization.

Human microglia play a pivotal role in neurological diseases, but few targeted therapies that directly modulate microglial state or function exist due to an incomplete understanding of microglial heterogeneity. We use single-cell RNA sequencing to profile live human microglia from autopsies or surgical resections across diverse neurological diseases and central nervous system regions. We observe a central divide between oxidative and heterocyclic metabolism and identify subsets associated with antigen presentation, motility, and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and leverage our dataset as a classification resource, finding that iPSC model systems recapitulate substantial in vivo heterogeneity. Finally, we identify and validate candidates for chemically inducing subtype-specific states in vitro, showing that Camptothecin downregulates the transcriptional signature of disease-enriched subsets and upregulates a signature previously shown to be depleted in Alzheimers.

neuroscience↗

bioRxiv2021

Intra- and inter-specific density dependence of body condition, growth, and habitat temperature in chub mackerel (Scomber japonicus)

The density dependence of growth and body condition have important impacts on fish population dynamics and fisheries management. Although population density is known to affect the temperature of the habitat selected, how this affects the density dependence of growth and body condition remains unclear. Here, we investigated annual changes in body condition, habitat temperature, and cohort-specific growth of chub mackerel (Scomber japonicus) in the western North Pacific and examined quarterly changes in the density dependence of body condition. We hypothesized that chub mackerel body condition is affected both directly (e.g., through competition for food) and indirectly (through changes in habitat temperature) by the abundance of both conspecifics (i.e., chub mackerel) and heterospecifics (the Japanese sardine Sardinops melanostictus). Indeed, chub mackerel body condition, habitat temperature, and growth all decreased with increasing conspecific and heterospecific abundance. Mean annual growth rates in chub mackerel were positively corelated with body condition. The best model showed that conspecific and/or heterospecific abundance had strong negative effects on chub mackerel body condition in all seasons, and influenced habitat temperature in some seasons. By contrast, temperature effects on body condition were weak. Therefore, direct effects likely have more impact than indirect effects on density-dependent body condition and growth.

ecology↗

bioRxiv2020

Multi-cellular communities are perturbed in the aging human brain and with Alzheimer's disease

The role of different cell types and their interactions in Alzheimers disease (AD) is an open question. Here we pursued it by assembling a high-resolution cellular map of the aging frontal cortex by single nucleus RNA-seq of 24 individuals with different clinicopathologic characteristics. We used the map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA-seq, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including inhibitory neuronal subtypes and oligodendroglial states. We further recovered a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.

neuroscience↗

bioRxiv2019

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression

Complexity of cell-type composition has created much skepticism surrounding the interpretation of brain bulk-tissue transcriptomic studies. We generated paired tissue genome-wide gene expression data and immunohistochemistry data, enabling us to assess statistical methods for modeling and estimating cellular heterogeneity in the brain. We demonstrate that several algorithms that rely on single-cell and cell-sorted data to define cell marker gene sets yield accurate relative and absolute estimates of constituent cell-type proportions.

neuroscience↗

bioRxiv2019

BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 implicated in Tau pathology

Identified as an Alzheimers disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear. Utilizing antibodies targeting specific BIN1 epitopes in human postmortem tissue and analyzing RNA expression data from purified microglia, we identified three isoforms expressed specifically in neurons (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed. Peptides contained in exon 7 of BIN1s N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau pathology. Since only isoforms 1, 2 and 3 contain exon 7, it appears that decreased protein expression of the N-BAR domain of BIN1 is associated with greater accumulation of tau pathology and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant, suggesting that targeting specific BIN1 isoforms might be a novel therapeutic approach to prevent the accumulation of tau pathology.

cell biology↗