Clusterin regulates microglial inflammation and cognitive function independent of amyloid pathology in Alzheimer's disease

Authors

Rawal, P., Moon, H.-J., Nguyen, V., Khatri, S., Larson, M. A., Vivian, J. C., Saido, T. C., Zhao, L.

Abstract

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Aug 2026.

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