Brain aging is associated with decline in synapse number and activity. Astrocyte is the central player in maintaining synapse homeostasis. However, the impact of astrocyte aging on synaptic dysfunction and cognitive decline remains unclear. Here, we identified a hallmark of aging astrocytes—Senescent Astrocytic Deposits (SAD) observed at aged rodents and macaques hippocampal astrocytic processes —that is associated with tripartite synapse dysfunction and memory decline. Importantly, SAD are markedly accelerated in mice lacking NRBF2, a gene whose coding product is a component of PI3KC3 complex required for autophagy and phagocytosis. Microdissection-coupled mass spectrometry, 3D electronic microscopy and spatial transcriptome analysis on NRBF2-deficient mice reveal SAD are abnormal protein deposits at the processes of ApoE-high expression astrocyte subtype and associated with dysfunctional tripartite synapses. Notably, astrocyte specific NRBF2 deletion induces reduced phagocytic activity, SAD formation, synaptic plasticity impairment, and memory deficits. Furthermore, enhancing astrocytic phagocytosis through astrocyte-specific RAB7 overexpression mitigates SAD formation, emphasizing the phagocytic activity-dependent role of astrocytes in maintaining synaptic homeostasis and cognitive function. Our findings establish SAD as a potential marker of astrocyte aging and underscore the critical role of astrocytic NRBF2 in preserving synaptic homeostasis and cognitive function during aging. We anticipate our finding to be a basis for developing new diagnostic and therapeutic avenues against brain aging and neurodegenerative diseases by targeting SAD.
Acknowledgements:
This study was supported by the following grants: Science and Technology Development Fund, Macau SAR (File no. 0040/2024/RIB1, 0025/2022/A1), National Natural Science Foundation of China (No. 82271455) and the University of Macau grants (File no. MYRG-GRG2024-00238-ICMS-UMDF, MYRG-GRG2023-00089-ICMS-UMDF) awarded to Jia-Hong Lu