Loss of GABAB receptor 1 signaling facilitates activation of disease‐associated microglia in the mouse model of Alzheimer’s disease

Abstract Background Disease‐associated microglia (DAM), which cluster around Aβ plaques, represent a significant pathological hallmark of Alzheimer’s disease (AD) and play a complex role in influencing neuroinflammation, mediating synapse loss, and participating in the phagocytic clearance of Aβ. Nonetheless, the precise mechanisms by which microglial activation extends beyond the traditional M1 and M2 classifications, encompassing a diverse spectrum of states, especially for DAM, closely intertwined with physiological and pathological conditions under Alzheimer’s circumstances remain elusive. Method Here, we first combined biochemical techniques and bioinformatic analysis to test and quantify the expression of GABA B R1 in both human and mouse AD models. Next, primary microglial cultures, siRNAs, immunohistochemistry, EEG recording and behavior tests were also used for in vitro and in vivo tests of loss of GABA B R1 signaling in DAM activation, AD‐like pathology, and sleep impairment in this study. Result Firstly, we identified that the mRNA expression and protein levels of GABA B receptor 1 (GABA B R1) deceased in microglia in the AD brain, especially in DAM compared to resting microglia. Next, we found that Aβ treatment directly lowered GABA B R1 expression in microglia. We further found that knocking down GABA B R1 in microglia decreased Trem2 expression, which increases the risk of Alzheimer’s pathogenesis. On the contrary, activating GABA B R1 in microglia increased C1qb levels. Notably, the administration of 3xTg mice with the GABA B R1 agonist cerebrolysin significantly not only restored microglial shape in the mPFC and hippocampus, with fewer branches but also reduced Aβ and hyperphosphorylation of tau levels in the mPFC and hippocampus and improved behavioral deficits and sleep impairment in AD mice. Conclusion Our findings delineate a novel role of loss of the GABA B R1 signaling in AD‐associated DAM activation, and elevating GABA B R1 activity within DAM holds promise for enhancing microglial structure and function, ultimately alleviating AD‐like pathology and behavioral deficits in the mouse model of Alzheimer’s disease.