Introduction: Alzheimer's disease (AD) is a neurodegenerative disease and the main cause of dementia in the elderly. AD pathology is characterized by accumulation of microglia around the beta-amyloid (Aβ) plaques which assumes disease-specific transcriptional signatures, as for the disease-associated microglia (DAM). However, the regulators of microglial phagocytosis are still unknown.
Methods: We isolated Aβ-laden microglia from the brain of 5xFAD mice for RNA sequencing to characterize the transcriptional signature in phagocytic microglia and to identify the key non-coding RNAs capable of regulating microglial phagocytosis. Through spatial sequencing, we show the transcriptional changes of microglia in the AD mouse brain in relation to Aβ proximity.
Results: Finally, we show that phagocytic messenger RNAs are regulated by miR-7a-5p, miR-29a-3p and miR-146a-5p microRNAs and segregate the DAM population into phagocytic and non-phagocytic states.
Discussion: Our study pinpoints key regulators of microglial Aβ clearing capacity suggesting new targets for future therapeutic approaches.
Keywords: Alzheimer's disease; microRNAs; microglia; phagocytosis; post-transcriptional regulation.
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.