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CD22 regulates Aβ clearance in microglia through INPP5D signaling
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DOI：10.3389/fncel.2026.1886995.png)
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Abstract
En 中文
IntroductionImpaired 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.MethodsWe investigated the role of CD22 in microglial Aβ processing using primary microglia; transcriptomic profiling; and hippocampal samples from AD patients and transgenic mice.ResultsWe 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.DiscussionCollectively; these findings identify a regulatory mechanism controlling intracellular Aβ degradation and suggest the CD22-INPP5D axis as a potential therapeutic target for AD.
Keywords:
Alzheimer's disease
CD22
Aβ clearance
INPP5D
primary microglia
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