Microglial repopulation reverses cognitive-associated deficits in an Alzheimer’s disease model by restoring the BDNF signaling

Over the past decade, genetic evidence has demonstrated that microglial dysregulation is likely to play a central role in the development of Alzheimer's disease (AD). As resident immune cells in the brain, microglia become dystrophic and senescent during the chronic progression of AD. To explore whether replenishing the brain with new microglia is beneficial to AD, we employed a CSF1R inhibitor PLX3397 to deplete microglia and induce repopulation after the inhibitor withdrawal in 5xFAD transgenic mice. We observed that microglial repopulation ameliorates AD-associated cognitive deficits, accompanied by elevation of synaptic proteins and hippocampal long-term potentiation (LTP). In addition, microglial morphology is restored after microglial self-renewal, and amyloid pathology is reduced with long-term repopulation but not short-term. Transcriptome analysis showed that repopulating microglia in 5xFAD mice recovers a gene expression profile that is highly similar to microglia from WT mice. Notably, the neurotrophic signaling pathway and hippocampal neurogenesis dysregulated in the AD brain are restored after microglial replenishment. At last, we confirmed that microglial repopulation rescues brain-derived neurotrophic factor (BDNF) expression to contribute to synaptic plasticity. Together, we conclude that microglial self-renewal benefits AD brain by restoring the BDNF neurotrophic signaling pathway. Thus, the proper replenishment of microglia may be an effective and novel therapeutic strategy for ameliorating cognition impairment in AD. 1. Four-month-old 5×FAD mice were fed with PLX3397 (Selleck, S7818, 290 mg/kg formulated in standard chow) for one month, then discontinued from PLX3377 feed and treated with a normal mouse diet for an additional one month, resulting in microglial repopulation. 2. Microglia (CD45lowCD11b+) were isolated from the hippocampi of WT and 5xFAD mice with or without microglial repopulation. Microglial RNA was extracted from the indicated groups for RNA sequencing.