Increasing the vitamin C transporter SVCT2 in microglia improves synaptic plasticity and restrains memory impairments in Alzheimer's disease models

Alzheimer's Disease (AD) is characterized by progressive cognitive decline and synaptic dysfunction, often associated with amyloid-beta accumulation and microglial alterations. Here, we investigate the role of the Sodium-dependent Vitamin C Transporter 2 (SVCT2) in microglia to modulate AD-like pathology in mice. Using a combination of RNA sequencing, advanced quantitative proteomics, electrophysiology, behavioral tests, high-throughput imaging, and microglial viral gene delivery, we explore the interplay between SVCT2 expression in microglia, amyloid-beta load, synaptic proteome changes, and synaptic plasticity. Our results demonstrate that SVCT2 expression in microglia decreases with age in the 5xFAD mice, correlating with memory deficits and alterations in synaptic mitochondrial proteome. Importantly, overexpression of SVCT2 in microglia leads to enhanced clearance of amyloid plaques and reconfiguration of the mitochondrial proteome landscape in the synapses, improving synaptic long-term plasticity (LTP) and memory performance. Our findings underscore the SVCT2 overexpression in microglia as a potent strategy to simultaneously decrease amyloid pathology and enhance synaptic function and memory performance, offering new avenues for therapeutic interventions in AD.