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

Pena-Ramos, O.; Gedam, M.; Zhang, X.; Wang, S.; Qi, C.; Huang, T.-H.; Rajpurohit, C.; Dunlap, M.; Deng, Y.; Auld, N.; Jung, S. Y.; Li, H.; Li, J.; Luo, L.; Peng, J.; Cheng, C.; Zheng, H.

doi:10.64898/2025.12.05.692670

bioRxiv · 10.64898/2025.12.05.692670

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

Pena-Ramos, O.·Gedam, M.·Zhang, X.·Wang, S.·Qi, C.·Huang, T.-H.·Rajpurohit, C.·Dunlap, M.·Deng, Y.·Auld, N.·Jung, S. Y.·Li, H.·Li, J.·Luo, L.·Peng, J.·Cheng, C.·Zheng, H.

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Abstract

Abstract/SummaryThe development of {beta}-amyloid (A{beta}) pathology in Alzheimers 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 A{beta} 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 {gamma}-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 A{beta} 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.

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Pena-Ramos, O., Gedam, M., Zhang, X., Wang, S., Qi, C., Huang, T.-H., Rajpurohit, C., Dunlap, M., Deng, Y., Auld, N., Jung, S. Y., Li, H., Li, J., Luo, L., Peng, J., Cheng, C., Zheng, H.. 2025-12-09. Astrocyte cell-surface proteomics identified CD44 as an OPN/SPP1 receptor regulating lipid metabolism and glial crosstalk in Alzheimer s disease. https://doi.org/10.64898/2025.12.05.692670

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