Carless, M. A. | Search bioRxiv

bioRxiv2026

A Cell-Type-Resolved Meta-Analysis Reveals Glial DNA Methylation Changes Associated with Aging and Alzheimer's Disease

Epigenome-wide association studies implicate DNA methylation in the development and progression of Alzheimers disease (AD). Although recent studies show that the epigenetics of non-neuronal cell types contribute to disease risk, the role of the methylome in individual glial cell types (i.e., astrocytes, oligodendrocytes) in biological aging and AD pathogenesis is unclear. In this study, we examined archived DNA methylation data across 13 cohorts and performed cell type deconvolution in silico to identify novel epigenetic signatures associated with aging and AD in glial cells. We observed pronounced age-associated methylation in astrocytes within the prefrontal cortex, whereas oligodendrocytes of the entorhinal cortex show the most differential methylation with AD status. Astrocytes, along with neurons, within the prefrontal cortex, emerge as key players in Braak stage-associated methylation, exhibiting strong concordance with previously reported associations at the brain tissue level. Age-associated changes in oligodendrocytes exhibit strong directional correlation with, and amplification of age-related effects with AD that affect neurodevelopmental processes, while AD-related methylation changes at age-associated sites in astrocytes diverge from those representative of normative aging processes. Our study expands on previous findings and reveals glial-specific methylation patterns associated with epigenetic aging and AD.

genomics↗

bioRxiv2024

An Efficient Direct Conversion Strategy to Generate Functional Astrocytes from Human Adult Fibroblasts

Direct reprogramming approaches offer an attractive alternative to stem-cell-derived models, allowing the retention of epigenetic information and age-associated cellular phenotypes, and providing an expedited method to generate target cell types. Several groups have previously generated multiple neuronal subtypes, neural progenitor cells, oligodendrocytes, and other cell types directly from fibroblasts. However, while some groups have had success at the efficient conversion of embryonic fibroblasts to astrocytes, they have not yet achieved similar conversion efficiency for adult human fibroblasts. To generate astrocytes for the study of adult-stage disorders, we developed an improved direct conversion strategy employing a combination of small molecules to activate specific pathways that induce trans-differentiation of human adult fibroblasts to astrocytes. We demonstrate that this method produces mature GFAP+/S100{beta}+ cells at high efficiency (40-45%), comparable to previous studies utilizing embryonic fibroblasts. Further, Fibroblast-derived induced Astrocytes (FdiAs) are enriched for markers of astrocyte functionality, including ion-channel buffering, gap-junction communication, and glutamate uptake; and exhibit astrocyte-like calcium signaling and neuroinflammatory phenotypes. RNA-Seq analysis indicates a close correlation to human brain astrocytes and iPSC-derived astrocyte models. Fibroblast-derived induced astrocytes provide a useful tool in studying the adult brain and complement existing in vitro models of induced neurons (iNs), providing an additional platform to study adult-stage brain disorders.

neuroscience↗