Clusterin Dynamics in Alzheimer’s Disease

Clusterin, also known as apolipoprotein J, is a multifunctional glycoprotein with prominent extracellular chaperone activity and a lesser-understood intracellular presence under stress conditions. In Alzheimer’s disease (AD), clusterin influences amyloid-β aggregation, clearance and toxicity, modulates immune responses and interacts with lipid carriers and cell-surface receptors. Genetic variants in the CLU gene rank among the strongest risk factors for late-onset AD and appear to alter both plasma and central nervous system concentrations of clusterin, impacting blood–brain barrier integrity, neuroinflammation and synaptic function. The dynamic interplay between secreted and intracellular clusterin isoforms, its regulation by single-nucleotide polymorphisms and its involvement in pathways of proteostasis and neurovascular health underscore its emerging role as both a biomarker and a potential therapeutic target in AD.

Research from Nature Portfolio

Large-scale genotypic and neuroimaging analyses have elucidated how common CLU variants influence amyloid deposition and brain structure. Specific alleles at several CLU loci were found to correlate with elevated cerebral amyloid-β load on positron emission tomography and reduced hippocampal volume on magnetic resonance imaging. These associations held across cognitively normal, mild cognitive impairment and AD cohorts, suggesting that CLU genotype may modulate early amyloid pathology and regional atrophy. By linking genetic risk to in vivo imaging endophenotypes, this work provides a framework for stratifying individuals according to CLU-driven amyloid vulnerability and for evaluating candidate interventions aimed at restoring clusterin-mediated proteostasis.

Clusterin Dynamics in Alzheimer’s Disease publication trend

The graph below shows the total number of articles in clusterin dynamics in alzheimer’s disease across all publications each year (not limited to Nature Index journals).

Technical terms

Clusterin: A secreted glycoprotein with extracellular chaperone function and intracellular stress-related roles.

Amyloid-β (Aβ): A peptide that aggregates into plaques and contributes to neurotoxicity in AD.

Chaperone activity: The ability of a protein to bind misfolded polypeptides and prevent aggregation.

Single-nucleotide polymorphism (SNP): A single base-pair variation in the genome that may influence gene function or expression.

Cerebral amyloid angiopathy (CAA): Deposition of amyloid-β in cerebral blood vessels, leading to microbleeds and vascular damage.

Oligodendrocyte progenitor cell (OPC): A precursor cell that differentiates into myelinating oligodendrocytes in the central nervous system.

Blood–brain barrier (BBB): A selective vascular interface that regulates passage of molecules and cells between the blood and the brain.

References

1. Alzheimer’s disease-associated complement gene variants influence plasma complement protein levels. Journal of Neuroinflammation (2023).
2. The presence of circulating human apolipoprotein J reduces the occurrence of cerebral microbleeds in a transgenic mouse model with cerebral amyloid angiopathy. Alzheimer's Research & Therapy (2024).
3. Astrocytic response mediated by the CLU risk allele inhibits OPC proliferation and myelination in a human iPSC model. Cell Reports (2023).
4. Clusterin in Alzheimer’s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies. Frontiers in Neuroscience (2019).
5. Clusterin Has Chaperone-like Activity Similar to That of Small Heat Shock Proteins*. Journal of Biological Chemistry (1999).
6. Clusterin protects neurons against intracellular proteotoxicity. Acta Neuropathologica Communications (2017).
7. Clusterin Is a Ligand for Apolipoprotein E Receptor 2 (ApoER2) and Very Low Density Lipoprotein Receptor (VLDLR) and Signals via the Reelin-signaling Pathway*. Journal of Biological Chemistry (2013).
8. Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk. Molecular Neurodegeneration (2012).
9. Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer’s disease cohorts. Scientific Reports (2016).