Clusterin

Clusterin (CLU) is an exercise-induced hepatokine and extracellular chaperone that suppresses neuroinflammation by inhibiting the complement cascade in brain endothelial cells and facilitates the clearance of pathogenic proteins like amyloid-β and α-synuclein PMID 40818821PMID 39818278PMID 38249295. As a critical mediator of the benefits of exercise on the brain, elevated circulating CLU levels are essential for the transfer of neuroprotective effects with studies showing that its depletion abolishes the cognitive improvements typically conferred by physical activity PMID 38393277PMID 38249295.

• Anti-inflammatory Signaling: Clusterin binds to brain endothelial cells (BECs) where it suppresses the expression of neuroinflammatory genes. Specifically, it inhibits the complement cascade PMID 40818821PMID 39818278PMID 38393277.
• Protein Clearance and Chaperoning: It facilitates the clearance of Amyloid-β (Aβ) peptides across the blood–brain barrier (BBB), preventing their aggregation into toxic plaques PMID 38393277. In the context of Parkinson's disease, CLU limits the uptake of extracellular α-synuclein aggregates by astrocytes; however, this advances the spread of pathology PMID 38249295.
• Synaptic Modulation: CLU promotes excitatory synaptic transmission and increases dendritic spine density, which are essential for maintaining cognitive function. Its presence in astrocytes is sufficient to rescue impaired synaptic structure in neurodegenerative models PMID 38249295.

Clusterin is classified as an exerkine (primarily a hepatokine, though also expressed in muscle) because its circulating levels are modulated by physical activity, and it has been identified as a necessary mediator of exercise-induced neuroprotection.

• Exercise-Induced Secretion: Plasma levels of clusterin significantly increase following chronic exercise training and correlate positively with improved aerobic ability PMID 38393277.
• Mediator of Plasma Benefits: Research demonstrates that transferring plasma from exercising mice to sedentary mice confers neuroprotective and anti-inflammatory benefits PMID 38393277PMID 35304603. In other studies depleting clusterin from this plasma abolishes these cognitive effects, confirming its role as a critical transducer of the systemic benefits of exercise to the brain PMID 38249295.

• Alzheimer’s Disease (AD) & Neuroinflammation: By inhibiting the complement cascade and facilitating Aβ clearance, clusterin mitigates neuroinflammation in the hippocampus PMID 39818278PMID 38393277. Peripheral administration of recombinant clusterin has been shown to reduce brain amyloid levels in AD mouse models PMID 38249295.
• Parkinson’s Disease (PD): Interestingly, CLU advances PD progression by inhibiting the astrocytic uptake and propagation of α-synuclein fibrils PMID 38249295.
• Pathological Complexity (Tau): While protective against amyloid and inflammation, CLU may have a dual role regarding Tau pathology. Upregulated CLU can lead to the formation of Tau/Clusterin complexes that facilitate the entry of Tau into cells via endocytosis, potentially accelerating the spread of Tau pathology in early-stage AD. This suggests that therapeutic strategies involving CLU must be carefully timed relative to disease progression PMID 38249295.

1. Neurological Disorders and Brain Injury

• Alzheimer’s Disease (AD): CLU is a major genetic risk factor for late-onset AD, influencing amyloid-β (Aβ) aggregation and clearance PMID 40322539. Recent discoveries indicate that CLU interacts with CD33 to modulate microglial phagocytosis and AD risk PMID 40766450. Interestingly, a novel small molecule enhancer of secreted CLU, DDL-357, has been shown to reduce phospho-tau and improve memory in murine models PMID 40322539. However, other studies suggest glycosylated CLU species may actually facilitate Aβ toxicity in neurons PMID 36329114.
• Brain Injury: In hemorrhagic brain injury, the Low-Density Lipoprotein Receptor (LDLR) interacts with CLU to promote a shift in astrocytes from a neurotoxic (A1) to a neuroprotective (A2) phenotype, ameliorating injury PMID 41175961.
• Other Conditions: CLU polymorphisms and plasma levels are associated with Multiple Sclerosis susceptibility and progression PMID 40289563. Conversely, in the auditory system, deletion of CLU protects against aminoglycoside-induced hair cell loss, suggesting inhibition is preferable for hearing preservation PMID 34194490.

2. Oncology: Resistance and Progression

• Drug Resistance: High CLU expression is linked to therapeutic resistance in colorectal cancer PMID 38319453, non-small-cell lung cancer PMID 34295670, and head and neck squamous cell carcinoma (HNSCC), where it counteracts oxidative stress PMID 39905539. In pancreatic cancer, CLU mediates the refractory response to MEK inhibitors PMID 36694355 and promotes proliferation by inhibiting cellular senescence PMID 35397747.
• Tumor Promotion: CLU facilitates glioma progression via BCL2L1-dependent apoptotic resistance PMID 40606578 and promotes glioblastoma stem cell resistance to temozolomide via macrophage polarization PMID 40128761. In osteosarcoma, CLU+ endothelial cells are key players in metastasis PMID 40623412.
• Therapeutic Inhibition: Silencing CLU sensitizes hepatocellular carcinoma cells to treatment PMID 41288878 and enhances the efficacy of berberine and zinc in colorectal cancer PMID 36394793.
• Protective Role: Contrasting its usual oncogenic role, secreted CLU functions as a tumor suppressor in meningioma by modulating macrophage polarization and the interferon pathway PMID 38416702.

3. Cardiovascular and Metabolic Diseases

• Heart Failure: CLU overexpression improves diastolic function and reduces fibrosis in heart failure with preserved ejection fraction (HFpEF) by inhibiting the UCHL1-NLRP3 inflammasome axis PMID 41608024.
• Atherosclerosis & Cardiotoxicity: CLU ameliorates diabetic atherosclerosis by suppressing macrophage pyroptosis PMID 40337510. It also protects cardiomyocytes from doxorubicin-induced apoptosis via the PI3K/AKT pathway PMID 40671119 and heat shock response PMID 40177418.
• Liver Disease: In liver fibrosis, secreted CLU drives fiber endocytosis by mesothelial cells, effectively resolving fibrosis PMID 41369634. CLU also inhibits lipopolysaccharide-induced liver injury PMID 39966409. However, in the context of Type 2 diabetes, hepatocyte-specific knockout of ApoJ improves metabolic profiles and prevents steatosis PMID 41441003.

4. Other Therapeutic Applications

• Ophthalmology: Recombinant human CLU shows promise as a biotherapeutic for dry eye disease by sealing ocular surface barrier damage PMID 36674497PMID 40661590 and normalizing retinal sterol levels in glaucoma models PMID 37392222.
• Musculoskeletal: CLU protects chondrocytes in osteoarthritis against apoptosis and inflammation PMID 38982592, though some studies suggest elevated levels correlate with disease activity in rheumatoid arthritis PMID 34075162.
• Kidney & Reproductive: CLU may serve as a viable therapeutic target for both diabetic kidney disease PMID 40438587 and diabetic nephropathy PMID 39630345. In reproductive health, CLU-carrying extracellular vesicles help restore ovarian function in premature ovarian failure of mouse models PMID 39272156.