It is increasingly evident that rodent microglia may not faithfully mirror the biology of their human counterparts, as recent transcriptomic studies have revealed substantial differences, including the abundant expression of specific immune genes in human microglia that are not part of the mouse microglial signature (17, 29, 30). Human microglia can be derived from human iPSCs (30–34); they serve as an excellent model system for studying neuroimmune interactions (30, 35, 36). When human iPSCs differentiated into microglia were exposed to brain substrates, including synaptosomes, myelin debris, apoptotic neurons, or synthetic β amyloid fibrils, it resulted in a variety of transcriptional changes (37). These changes corresponded to gene signatures found in human brain microglia, particularly those enriched in neurodegenerative diseases (37). Therefore, human iPSC-derived microglia could be used as an in vitro model to understand disease-relevant cellular phenotypes. Despite the involvement of microglia in the pathophysiology of AUD (27, 38–40), the specific cellular and molecular mechanisms that govern the interaction between ethanol exposure and AUD PRS in the human context remain unknown.
