AN ACIDOSIS-SENSING PATHWAY IMPAIRS MICROGLIAL LYSOSOMAL FUNCTION TO DRIVE WHITE MATTER INJURY AND COGNITIVE DECLINE IN CHRONIC CEREBRAL HYPOPERFUSION

Chronic cerebral hypoperfusion (CCH) is a central pathological feature of vascular dementia (VaD), yet the specific cellular mechanisms linking hypoperfusion to cognitive decline remain incompletely understood. Using the bilateral common carotid artery stenosis (BCAS) mouse model, this study investigated the role of microglial lysosomal function in CCH‑induced brain injury. Behavioral tests showed that BCAS specifically impaired spatial learning and memory in the Morris water maze, while locomotor activity (open field test) and motor coordination (rotarod test) remained unaffected. Neuropathological analysis revealed that BCAS induced significant white matter demyelination, synaptic loss, and pronounced microglial activation.
We systematically evaluated microglial function before and after model establishment. Results showed that following modeling, microglial lysosomal acidification and degradation capacity were impaired, leading to significantly reduced clearance of myelin debris and a shift toward a pro‑inflammatory phenotype. Modulation of the acidosis‑sensing signaling pathway restored microglial phagocytic function, which substantially alleviated neuroinflammation, preserved white matter integrity, reduced synaptic loss, and ultimately markedly slowed cognitive decline. These findings demonstrate that the acidosis‑sensing signaling pathway plays a key role in mediating neuroinflammation and white matter damage induced by CCH through the regulation of microglial function, thereby revealing a novel therapeutic target for vascular cognitive impairment.