DNA Methylation Signatures of Alzheimer's Disease in Aged Astrocyte

PROJECT SUMMARY/ABSTRACT Age-related neurological disorders like Alzheimer’s disease (AD) affect millions worldwide and pose a major burden to the healthcare system. While most studies focus on neuronal degeneration in AD, there is substantial evidence that non-neuronal cells, such as astrocytes, play an important role in disease progression. Importantly, a major risk factor for late-onset AD, APOE, is highly expressed in astrocytes and is a major contributor to amyloid-beta-associated cellular toxicity, which in turn, dysregulates astrocytic functionality. While the etiological basis for AD in disease-associated astrocytes is unclear, epigenetic modifications like DNA methylation (DNAm), which are known contributors to both healthy aging and neurodegeneration, are likely to play a role. While induced pluripotent stem cell (iPSC)-derived models of AD provide valuable insight into the molecular basis for the disease, they lack the inherent ability to recapitulate age-associated DNA methylation, transcription, and cellular phenotypes that are highly relevant in such late-stage, age-associated brain disorders. Studies show that direct conversion of fibroblasts to neurons retains such age-associated methylomic and transcriptomic patterns. We therefore developed an efficient direct conversion strategy of adult human fibroblast-derived induced-astrocytes (FDIAs), which we propose to validate as an “age-in-a-dish” model that captures age- associated DNA methylation, gene expression, and cellular phenotypes. Using this model, we also aim to elucidate the association of age- and disease-related changes in DNAm to astrocyte functionality using the following aims: 1) establish age-associated DNAm and transcriptional signatures and cellular phenotypes of FDIAs; and 2) evaluate the relationship between DNAm and astrocytic function and elucidate their contribution to AD risk. Through this research, we expect to efficiently develop an ‘age-in-a-dish’ model of human astrocytes that accurately captures age-associated DNAm and transcriptional signatures, which we will be assessed for their role in neuroinflammatory and neurodegenerative processes in AD. Our study is unique in both the validation of an aged astrocyte model (FDIAs), and in the evaluation of astrocytic DNAm and transcriptional signatures in AD, thus improving our understanding of the molecular etiology of age-related brain disorders, including AD.