Biology subjects

Tsai, A. P.-Y.

Publications and source records attributed to Tsai, A. P.-Y..

3 recordsLinked to original sources

bioRxiv2025

Simultaneous analysis of single-cell gene expression and morphology provides new insight into how microglia change with age

Cellular morphology is intimately connected with function. While the link between morphology and functional states has been studied extensively, the role of subcellular transcript localization in cellular function remains unclear. Here we use microglia, the brains resident macrophages, as a model to dissect the interaction of morphology, transcript localization, and function. Using multiplexed error-robust fluorescence in situ hybridization combined with fluorescent immunohistochemistry, we analyzed transcript distribution and morphology simultaneously in young and aged mouse brains. Our approach revealed how mRNA spatial organization varies across microglial states. We identified distinct transcript localization patterns within microglial processes and uncovered morphological heterogeneity within transcriptomically defined populations. Notably, we found a subpopulation of disease-associated microglia with a ramified morphology (displaying numerous processes), challenging the conventional assumption between morphology and microglial states. Finally, we found that aging not only alters the distribution of compartmentalized mRNAs but also reshapes their colocalization networks, shifting microglial functions from synaptic maintenance and phagocytic processes in younger brains to migration and catabolic pathways in older brains. Our findings highlight the role of subcellular transcript organization in shaping microglial morphology and function, offering new avenues for studying and modulating microglial states in health, disease, and aging.

neuroscience↗

bioRxiv2023

APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia

Several genetic risk factors for Alzheimers Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar A{beta} (fA{beta}) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.

neuroscience↗

bioRxiv2020

INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia

BackgroundAlzheimers disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. MethodsWe performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimers Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. ResultsDifferential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. ConclusionsOur findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.

neuroscience↗