Abstract
<jats:title>ABSTRACT</jats:title> <jats:p>Clusterin (CLU) is a major genetic risk factor for late-onset Alzheimer’s disease (AD), yet the mechanism underlying this risk remains unclear. This study investigated the role of CLU in regulating microglial inflammation, amyloid pathology, and cognitive function in CLU-deficient and AD models. CLU synthesis and secretion in microglia were highly dynamic, with minimal expression at rest but markedly increased expression upon pro-inflammatory stimulation. CLU deficiency amplified microglial activation and inflammatory responses, whereas introducing recombinant CLU protein reduced microglial inflammation. In a human mutant APP knock-in AD mouse model, loss of CLU impaired learning and memory despite a reduced amyloid burden. snRNA-seq analysis further revealed that CLU loss disrupted the balance between excitatory and inhibitory neurons. These findings provide novel insights indicating that CLU likely functions as a negative feedback regulator of microglial activation and inflammation, thereby promoting microglial resolution and neuronal homeostasis, and consequently, cognitive outcomes independent of amyloid pathology.</jats:p>