Biology subjects

TCW, J.

Publications and source records attributed to TCW, J..

12 recordsLinked to original sources

bioRxiv2026

Context-dependent regulatory networks connect Alzheimer's disease genetics to microglial inflammatory responses

Inflammation is central to Alzheimer's disease (AD) pathogenesis. Microglia, the resident innate immune cells of the brain, exhibit diverse inflammatory states and are enriched for AD-associated genetic variants within active cis-regulatory elements (CREs). However, the interplay among genetic variants, transcription factor (TF)-CRE-gene programs, and microglial responses across inflammatory and disease contexts remain poorly understood. Here, we develop context-dependent epigenomic networks (cEpiNets), integrating bulk and single-nucleus assay for transposase-accessible chromatin using sequencing (ATAC-seq) to reconstruct regulatory programs across inflammatory, genetic perturbation, and disease contexts. Leveraging TF footprinting and graph embedding, cEpiNets identifies shared and context-specific programs and predicts regulatory circuits in unseen biological contexts. In a SORL1-marked inflammatory microglial state that expands during AD progression, cEpiNets annotates AD risk variants at the SORL1 locus and identifies variants associated with cellular state abundance across donors. Cross-context analysis further identifies ZBTB14, whose inflammation-associated program connects AD risk variant-harboring CREs to target genes and widespread TF remodeling in AD. Donor-level ZBTB14 footprint activity is negatively associated with AD pathology, while combined IFN{gamma}/TNF stimulation represses ZBTB14 and activates a subset of inferred targets. Collectively, cEpiNets bridges genetic variation, regulatory programs, and disease-associated cellular phenotypes to facilitate mechanistic interpretation of complex disease genetics.

bioinformatics↗

bioRxiv2026

MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease

The Alzheimers disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (A{beta}) pathology, and ameliorated the defects in synaptic marker expression in AppNL-G-F AD model mice. Mechanistically, miR-223 induced microglial clustering around A{beta} plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene SPPL2A, indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Factorization of Alzheimer's disease genetic risk influences allow patient stratification, predicting disease onset, cognitive decline, and cell-type specific responses

Late-onset Alzheimers disease (AD) is a complex and heterogeneous neurodegenerative disease with significant genetic components implicated in at least 97 loci from AD genome-wide association studies. While various distinct AD subtypes have been identified based on brain or CSF molecular profiling, contribution of the genetic signatures in distinguishing the AD subtypes is lacking. Here, we leveraged large snRNA-seq postmortem brain data with an empirical Bayes matrix factorization (EBMF) approach to study common effects of 197 AD risk variants on neuronal and glial cell transcriptome, enabling factor-based polygenic score (fPGS) and patient clustering based on their functional genetic profiles. We confirmed that each factor captures specific AD risk variant influences on cell types and known AD-associated biological processes, such as mitochondrial activity, endo-lysosomal activity, mRNA processing, neuroinflammation, or calcium signaling. Further, we found that most fPGS were predicting a certain neuropathological or AD-associated molecular condition. Notably, fPGS3 predicts somatic mutation burden in excitatory neurons, and fPGS7 predicts epigenome erosion in excitatory neurons associated with lipid transport disorders, increased mitochondrial activity, and increased Tau pathology. Finally, unsupervised clustering analysis of individuals with mild cognitive impairment and AD based on their fPGS profiles enable us to identify seven clusters, which are differentiated by the APOE genotype. Among them, five groups were subdivided within APOE3 homozygotes, which remarkably predicted either the disease severity or the disease onset with up to 6 years differences among groups. Resilient groups were associated with reduced matrisome and reactivity in astrocytes and increased cholesterol metabolic pathways in oligodendrocytes and OPCs. Overall, the analyses confirmed the ability of EBMF to stratify AD risk variant influences into molecularly and clinically coherent factors that allow genetic predictions of particular cell types and alterations of biological processes impacting the disease.

genomics↗

bioRxiv2025

Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia

The integrity and function of the blood-brain barrier (BBB) are largely regulated by pericytes. Pericyte deficiency leads to BBB breakdown and neurological dysfunction in major neurological disorders including stroke and Alzheimers disease (AD). Transplantation of pericytes derived from induced pluripotent stem cells (iPSC-PC) has been shown to restore the BBB and improve functional recovery in mouse models of stroke and pericyte deficiency. However, the molecular profile and functional properties of iPSC-PC under hypoxic conditions, similar to those found in ischemic and neurodegenerative diseases remain largely unexplored. Here, we demonstrate that iPSC-PC under severe hypoxia retain essential functional properties, including key molecular markers, proliferation rates, and the ability to migrate to host brain vessels via function-associated PDGFRB-PDGF-BB signaling. Additionally, we show that iPSC-PC exhibit similar clearance of amyloid beta (A{beta}) neurotoxins from AD mouse brain sections under both normoxic and hypoxic conditions. These findings suggest that iPSC-PC functions are largely resilient to hypoxia, highlighting their potential as a promising cell source for treating ischemic and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Divergent Effects of APOE3 and APOE4 Human Astrocytes on Key Alzheimer's Disease Hallmarks in Chimeric Mice

Despite strong evidence supporting that both astrocytes and apolipoprotein E (APOE) play crucial roles in the pathogenesis and progression of Alzheimers disease (AD), the impact of astrocytes carrying different APOE variants on key AD pathological hallmarks remains largely unknown. To explore such effects in a human relevant context, we generated a chimeric model of AD. We transplanted isogenic APOE3 or APOE4 human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains of AD model mice. We show that at five to six months after transplantation, transplanted cells have differentiated into mature astrocytes (h-astrocytes) that often integrate in upper layers of one cortical hemisphere. APOE3 and APOE4 h-astrocytes differentially express and secrete the APOE protein, which binds to A{beta} plaques with an isoform-dependent affinity. Remarkably, APOE3 h-astrocytes ameliorate A{beta} pathology, Tau pathology and neuritic dystrophy. In contrast, APOE4 h-astrocytes aggravate these AD processes. Moreover, APOE3 and APOE4 h-astrocytes modulate microglia responses to A{beta} pathology in opposite ways. APOE4 h-astrocytes enhance microglia clustering around A{beta} plaques and exacerbate DAM state whereas APOE3 h-astrocytes reduce microglia clustering and induce a more homeostatic state on plaque-associated microglia. These findings highlight a critical contribution of h-astrocytes not only to A{beta} pathology but also to other key AD hallmarks in chimeric mice. In addition, our findings reveal that h-astrocytes with different APOE variants and the different forms of APOE they secrete have a crucial role in AD progression.

neuroscience↗

bioRxiv2023

Molecular signature and functional properties of human pluripotent stem cell-derived brain pericytes

Brain pericytes maintain the blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic proteins. Their loss in neurological disorders leads to BBB breakdown, neuronal dysfunction, and cognitive decline. Therefore, cell therapy to replace lost pericytes holds potential to restore impaired cerebrovascular and brain functions. However, the molecular composition and function of human iPSC-derived brain pericytes (iPSC-PC) remains poorly characterized. Here, we show by a quantitative analysis of 8,344 proteins and 20,572 phosphopeptides that iPSC-PC share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes. This includes cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. In pericyte-deficient mice, iPSC-PC home to host brain capillaries to form hybrid human-mouse microvessels with ligand-receptor associations. They repair BBB leaks and protect against neuron loss, which we show requires PDGRFB and pleiotrophin. They also clear Alzheimers amyloid-{beta} and tau neurotoxins in an ex vivo brain slice assay via lipoprotein receptor. Thus, iPSC-PC may have potential as a replacement therapy for pericyte-deficient neurological disorders.

neuroscience↗

bioRxiv2023

ApoE4 drives maladaptive heterogeneity and immunometabolic responses of astrocytes

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimers disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

neuroscience↗

bioRxiv2020

Human iPSC-derived astrocytes transplanted into the mouse brain display three morphological responses to amyloid-β plaques

BackgroundIncreasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimers disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. MethodsTo address these challenges, we established an approach to study human astroglia within the context of the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived glia progenitors into neonatal brains of immunodeficient mice. ResultsXenografted (hiPSC)-derived glia progenitors differentiate into astrocytes that integrate functionally within the mouse host brain and mature in a cell-autonomous way retaining human-specific morphologies, unique features and physiological properties. In Alzheimers chimeric brains, transplanted hiPSC-derived astrocytes respond to the presence of amyloid plaques with various morphological changes that seem independent of the APOE allelic background. ConclusionIn sum, this chimeric model has great potential to analyze the role of patient-derived and genetically modified astroglia in Alzheimers disease.

neuroscience↗

bioRxiv2019

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease and progressive supranuclear palsy converge on altered glial regulation

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble -synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with -synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

neuroscience↗

bioRxiv2019

Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia

Apolipoprotein E (APOE) {varepsilon}4 is the strongest genetic risk factor for Alzheimers disease (AD). Although its association with AD is well-established, the impact of APOE {varepsilon}4 on human brain cell function remains unclear. Here we investigated the effects of APOE {varepsilon}4 on several brain cell types derived from human induced pluripotent stem cells and human APOE targeted replacement mice. Gene set enrichment and pathway analyses of whole transcriptome profiles showed that APOE {varepsilon}4 is associated with dysregulation of cholesterol homeostasis in human but not mouse astrocytes and microglia. Elevated matrisome signaling associated with chemotaxis, glial activation and lipid biosynthesis in APOE {varepsilon}4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted transcriptomic data from APOE {varepsilon}4 glia and AD post-mortem brains. Experimental validation of the transcriptomic findings showed that isogenic APOE {varepsilon}4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE {varepsilon}4 glia also secrete higher levels of proinflammatory chemokines, cytokines and growth factors, indicative of glial activation. Thus, APOE {varepsilon}4 induces human glia-specific dysregulation that may initiate AD risk.

neuroscience↗

bioRxiv2019

Integration of Alzheimer’s disease genetics and myeloid cell genomics identifies novel causal variants, regulatory elements, genes and pathways

Genome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimers disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD.

genomics↗

bioRxiv2017

An Efficient Platform For Astrocyte Differentiation From Human Induced Pluripotent Stem Cells

Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. Using this method, we generated hiPSC-derived astrocyte populations (hiPSC-astrocytes) from 42 NPC lines (derived from 30 individuals) with an average of [~]90% S100{beta}-positive cells. Transcriptomic analysis demonstrated that the hiPSC-astrocytes are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our novel protocol is a reproducible, straightforward (single media) and rapid (<30 days) method to generate homogenous populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders.\n\nABBREVIATIONS

neuroscience↗