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 <i>Spp1</i> , to promote lipid accumulation, and this effect is γ-secretase dependent. Astrocytic CD44 in turn regulated <i>Spp1</i> expression and microglial activity. Conditional deletion of <i>Cd44</i> 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.