Senescent astrocytic deposits drive cognitive decline by disrupting tripartite synapse in the aging brain

Abstract

Brain aging involves synapse decline, with astrocytes playing a key role in synapse homeostasis. However, the impact of astrocyte senescence on synaptic dysfunction and cognitive decline remains unclear. Here, we identified a hallmark of aging astrocytes Senescent Astrocytic Deposits (SAD) observed at aged rodents, macaques, and human hippocampal astrocytic processes that is associated with tripartite synapse dysfunction and memory decline. Laser capture microdissection-coupled mass spectrometry (LCM-MS), spatial transcriptome analysis and 3D electron microscopy revealed that SAD are abnormal protein deposits at the processes of ApoE-high expression astrocyte subtype and associated with dysfunctional tripartite synapses. Using a transgenic mouse (Nrbf2 knockout) with accelerated SAD formation as a tool for genetic manipulation, we clearly demonstrated that age-dependent defect of phagocytosis at maturation stage in astrocytic drives SAD accumulation, synaptic injury and cognitive deficits. Collectively, our findings establish SAD as a mechanistic link between astrocyte senescence and synaptic damage, underscoring the critical role of astrocytic phagocytic function in preserving synaptic homeostasis and cognitive function during aging.