Molecular and histological characterizations reveal two distinct senescent microglia populations in Niemann-Pick...

Niemann-Pick disease type C (NPC) is a rare autosomal recessive disorder characterized by progressive neurodegeneration, primarily caused by a functional defect in NPC1 resulting from gene mutations. NPC1, a lysosomal transmembrane protein, acts as a transporter of cholesterol from the lysosome to the endoplasmic reticulum, and its dysfunction results in the intracellular accumulation of unesterified cholesterol. Although microgliosis with accumulated cholesterol has been reported in NPC, the contribution of microglia to disease pathogenesis remains elusive. In this study, we demonstrated that microglia with increased cell numbers exhibit a cellular senescent phenotype in an NPC mouse model. Senescent microglia were transcriptionally and histologically segregated into two distinct major types, Cdkn1a⁺ and Cdkn2a⁺ subpopulations, with different cytokine and chemokine expression profiles. Notably, senescent microglia emerged specifically at sites of neuronal cell death in a region- and time-dependent manner. Our findings reveal previously unrecognized states of microglial senescence in the NPC mouse model and suggest that targeting senescent microglia provides a basis for a novel therapeutic strategy for NPC.