Astrocytic mGluR5-dependent calcium hyperactivity promotes amyloid-β pathology and cognitive impairment

Astrocytic dysfunction is a crucial factor in the pathogenesis of Alzheimer's disease. Metabotropic glutamate receptor 5 (mGluR5) is expressed ubiquitously in the brain and is a key molecule in regulating synaptic transmission and plasticity. It has been shown that mGluR5 is elevated in astrocytes in Alzheimer's disease. However, it remains elusive how astrocytic mGluR5 contributes to the pathogenesis of Alzheimer's disease. Here, we first quantified a high expression level of astrocytic mGluR5 in the hippocampus of Alzheimer's disease brains and demonstrated that the expression of astrocytic mGluR5 was positively correlated with Alzheimer's disease progression in both humans and mice. Upregulating astrocytic mGluR5 in the CA1 region at an early stage accelerated, whereas downregulating these receptors rescued, amyloid-β (Aβ) pathology and cognitive impairment in Alzheimer's disease mice. Moreover, the activation of mGluR5 led to calcium hyperactivity in astrocytes, causing Aβ pathology progression due to dysregulated Aβ uptake and degradation in astrocytes. Importantly, attenuating astrocytic calcium hyperactivity in the hippocampal CA1 region in the prodromal phase ameliorated Aβ pathology and cognitive defects in Alzheimer's disease mice. Our findings thus reveal a fundamental contribution of astrocytic mGluR5 in presymptomatic Alzheimer's disease that may serve as a potential diagnostic and therapeutic target for early Alzheimer's disease pathogenesis.