De-Zhi Zou, Jun Li, Qiu-Shuang Long, Ruo-Qi Zhang, Bing-Lin Zhu, Jia-Ze Tan
We identified CD22 as an Aβ-inducible signaling regulator that restrains microglial Aβ processing. CD22 expression was elevated in the hippocampus of AD patients and transgenic mice and was rapidly induced by Aβ in microglia. Functionally, CD22 knockdown enhanced intracellular Aβ degradation without affecting initial uptake. Transcriptomic profiling identified the AD risk gene INPP5D as a key downstream effector of CD22. Loss of CD22 suppressed INPP5D expression and promoted AKT activation, while INPP5D overexpression partially rescued the enhanced Aβ clearance phenotype. These findings define a CD22-INPP5D signaling axis that acts as a molecular brake on microglial Aβ processing. Aβ itself induces CD22 expression, revealing a feed-forward inhibitory loop in which amyloid accumulation limits its own clearance.
INTRODUCTION: Impaired microglial clearance of amyloid-β (Aβ) is a central driver of Alzheimer's disease (AD), yet the mechanisms governing intracellular Aβ degradation remain poorly defined.
METHODS: We investigated the role of CD22 in microglial Aβ processing using primary microglia, transcriptomic profiling, and hippocampal samples from AD patients and transgenic mice.
RESULTS: We identified CD22 as an Aβ-inducible signaling regulator that restrains microglial Aβ processing. CD22 expression was elevated in the hippocampus of AD patients and transgenic mice and was rapidly induced by Aβ in microglia. Functionally, CD22 knockdown enhanced intracellular Aβ degradation without affecting initial uptake. Transcriptomic profiling identified the AD risk gene INPP5D as a key downstream effector of CD22. Loss of CD22 suppressed INPP5D expression and promoted AKT activation, while INPP5D overexpression partially rescued the enhanced Aβ clearance phenotype. These findings define a CD22-INPP5D signaling axis that acts as a molecular brake on microglial Aβ processing. Aβ itself induces CD22 expression, revealing a feed-forward inhibitory loop in which amyloid accumulation limits its own clearance.
DISCUSSION: Collectively, these findings identify a regulatory mechanism controlling intracellular Aβ degradation and suggest the CD22-INPP5D axis as a potential therapeutic target for AD.