Disease-associated RNA and protein signatures in iPSC-derived microglia model of Alzheimer’s disease

Microglia, the primary immune cells of the brain, are essential for maintaining neural homeostasis. Dysfunction of microglia is strongly associated with neurodegenerative diseases, including Alzheimer’s disease (AD), yet the underlying molecular mechanisms remain incompletely understood. In this study, we compared microglia derived from induced pluripotent stem cells (iPSCs) of sporadic AD patients and healthy donors, identifying AD-associated alterations in mRNAs, proteins, and small non-coding RNAs (sncRNAs). Gene Ontology analysis of total RNA sequencing and proteomic data suggested significant dysregulation of pathways involved in extracellular communication, intracellular transport, cytoskeletal dynamics, and protein–protein interactions. Using a modified T4 PNK–sncRNA sequencing approach, we further identified disease-associated sncRNAs, including several previously uncharacterized species. Together, these findings highlight the utility of iPSC-derived microglia for modeling AD and uncover molecular alterations that may inform future therapeutic strategies.