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Publication
Neuron

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

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  • June 18, 2025
  • Tracy L. Young-Pearse, Brigham and Women's Hospital
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
Plasma

Highlights

  • AD-risk SNPs at the CLU locus selectively reduce CLU expression in astrocytes
  • Increased inflammatory proteins in CLU-deficient and AD CLU risk astrocytes
  • Microglia mediate CLU-dependent synapse reduction and increased tau phosphorylation
  • AD-protective CLU alleles disrupt the link between tau pathology and cognition

Summary

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.

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Authors & Affiliations

1 ∙ 1 ∙ 1 ∙ 1 ∙ 1 ∙ 4 ∙ 1 ∙ 1 ∙ 5 ∙ 5,6 ∙ 1 ∙ 1 ∙ 1 ∙ 4 ∙ 3 ∙ 2 ∙ 4 ∙ 4 ∙ 1,7 

  1. Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  2. Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA
  3. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
  4. Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
  5. Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, Irvine, CA, USA
  6. Department of Neurobiology and Behavior, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.