Astrocytic Caveolin-1 drives white matter injury via aberrant cathepsin D trafficking in vascular cognitive impairment

Abstract

Efficient clearance of myelin debris is essential for white matter repair in vascular cognitive impairment (VCI) caused by chronic cerebral hypoperfusion, but the underlying cell-specific mechanisms remain poorly defined. Here, we investigated the role of astrocytic Caveolin-1 (Cav-1) in regulating this process. Chronic cerebral hypoperfusion was induced by bilateral carotid artery stenosis in mice and CoCl 2 -induced hypoxia in primary astrocytes. Myelin uptake and degradation were assessed by immunofluorescence and flow cytometry. Lysosomal function was evaluated using DQ-BSA assays and lipid staining. Human relevance was examined using single-nucleus RNA sequencing of vascular dementia (VaD) white matter. Corpus callosum integrity was assessed by immunofluorescence and transmission electron microscopy, and cognitive function was evaluated using the Morris water maze. Astrocyte-specific Cav-1 knockout and cathepsin D ( Ctsd) knockdown were used to define molecular mechanisms. Chronic cerebral hypoperfusion induced progressive demyelination, accompanied by a shift from microglial to astrocytic myelin clearance. Under hypoxia, astrocytes displayed enhanced myelin uptake but impaired degradation, characterized by reduced lysosomal proteolysis and increased inflammatory signaling. Cav-1 was markedly upregulated in reactive astrocytes, and human VaD transcriptomic data revealed activation of caveolin-mediated endocytosis and lysosomal alterations. While Cav-1 did not affect early myelin uptake, its deletion restored lysosomal proteolysis, reduced neuroinflammation, and improved cognitive performance. Mechanistically, the scaffolding domain of Cav-1 interacts with proCTSD and promotes its secretion, thereby limiting CTSD maturation and lysosomal proteolytic capacity. Blocking this secretory pathway restored intracellular CTSD and enhanced myelin degradation. Notably, Ctsd knockdown abolished the beneficial effects of Cav-1 deletion, establishing a Cav-1/proCTSD-dependent mechanism. These findings identify a Cav-1–proCTSD axis that impairs astrocytic lysosomal proteolysis by redirecting CTSD from maturation to secretion, thereby driving neuroinflammation and white matter injury in VCI. Targeting this pathway may represent a therapeutic strategy for hypoperfusion-related white matter disorders.