Single-Nucleus Profiling Reveals a BBB Senescence Unit Driving AD Pathology in Human Brain

Cellular senescence contributes to Alzheimer's disease (AD) and involves the neurovascular unit, but the molecular mechanisms of cellular senescence in AD pathogenesis remain incompletely understood. Here, we integrate single-nucleus RNA sequencing data from 75 human brain samples to identify a coordinated BBB senescence unit of astrocytes, pericytes, microglia and T cells. Molecular profiling shows inflammatory signaling with maladaptive repair responses in senescent cells. Intercellular communication analysis identifies the SPP1-CD44 axis as central to BBB senescence in AD, with up-regulated SPP1 in senescent microglia and increased CD44 receptor levels in senescent astrocytes, creating a self-sustaining inflammatory loop. Network analysis reveals SPP1 as a hub gene consistently correlated with all AD pathological scores. The clinical significance of SPP1 is further validated in cerebrospinal fluid proteomics data from AD patients. These findings demonstrate that cellular senescence is a crucial pathological process in AD and specifically impacts neurovascular unit via the establishment of a BBB senescence unit.