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. 2025 Jun 18;113(12):1925-1946.e11.
doi: 10.1016/j.neuron.2025.03.034. Epub 2025 Apr 30.

CLU alleviates Alzheimer's disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density

Alexandra M Lish  1 , Elyssa F L Grogan  1 , Courtney R Benoit  1 , Richard V Pearse 2nd  1 , Sarah E Heuer  1 , Tain Luquez  2 , Gwendolyn A Orme  1 , Paige C Galle  1 , Giedre Milinkeviciute  3 , Kim N Green  4 , Kellianne D Alexander  1 , Seeley B Fancher  1 , Andrew M Stern  1 , Masashi Fujita  2 , David A Bennett  5 , Nicholas T Seyfried  6 , Philip L De Jager  2 , Vilas Menon  2 , Tracy L Young-Pearse  7
Affiliations

CLU alleviates Alzheimer's disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density

Alexandra M Lish et al. Neuron. .

Abstract

Genetic studies implicate clusterin (CLU) in the pathogenesis of Alzheimer's disease (AD), yet its precise molecular impact remains unclear. Through unbiased proteomic profiling and functional validation in CLU-deficient astrocytes, we identify increased nuclear factor κB (NF-κB)-dependent signaling and complement C3 secretion. Reduction of astrocyte CLU induced microglia-dependent modulation of extracellular apolipoprotein E (APOE) and phosphorylated tau, as well as increased microglial phagocytosis and reduced synapse numbers. By integrating mouse and human cellular models with comprehensive analyses of human plasma and brain tissue, we demonstrate that CLU AD-risk alleles are associated with reduced CLU protein and heightened inflammatory profiles. These findings establish a mechanistic link between AD genetic risk factors, astrocyte reactivity, and microglia-mediated effects on synaptic integrity. Collectively, these results support a model in which CLU upregulation in response to neuropathology is associated with maintenance of cognitive function, while diminished astrocyte CLU levels heighten disease susceptibility.

Keywords: APOE; Alzheimer’s disease; TAU; astrocyte reactivity; astrocyte-microglia crosstalk; clusterin; complement; human iPSC cells; risk variants; synapse density.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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