Astrocyte cell-surface proteomics identified CD44 as an OPN/SPP1 receptor regulating lipid metabolism and glial crosstalk in Alzheimer's disease.

The development of β-amyloid (Aβ) pathology in Alzheimer's disease (AD) is accompanied by profound changes in astrocytes and microglia. How these responses are orchestrated by cell surface proteins, key mediators of cell-cell communication, remain unclear. Using in situ astrocyte cell-surface proteome profiling in 5xFAD mice, we identified a set of dysregulated surface proteins induced by Aβ pathology, including CD44. CD44 was selectively upregulated in plaque-adjacent astrocytes and interacted with osteopontin (OPN), encoded by the disease-associated microglia gene Spp1 , to promote lipid accumulation, and this effect is γ-secretase dependent. Astrocytic CD44 in turn regulated Spp1 expression and microglial activity. Conditional deletion of Cd44 in adult astrocytes of 5xFAD mice attenuated glial reactivity, reduced Aβ pathology, and improved cognition. These findings define a plaque-proximal OPN-CD44 axis that controls astrocyte lipid metabolism and glial activity, positioning CD44 as a surface-accessible therapeutic target in AD.