Clusterin’s Double-Edged Role in Alzheimer’s: Promise and Caution

A recent breakthrough in neuroscience suggests that clusterin, a lesser-known but increasingly relevant protein, could become an essential ally in the fight against Alzheimer’s.

Researchers at Massachusetts General Hospital (Mass General Brigham) have identified how this cerebroprotective peptide could be key to curbing brain inflammation and preserving neuronal connections, paving the way for personalized treatments for neurodegenerative diseases. However, clusterin’s role is dual and changes depending on the stage of the disease, requiring careful analysis.

Clusterin Emerges as Both Protector and Potential Risk in Alzheimer’s Treatment Strategies

The results, published in Neuron, demonstrate that increasing clusterin (CLU) levels offers a distinct and complementary approach to anti-amyloid therapies for preventing cognitive decline by promoting brain resilience. Experiments in diverse models—brain tissue from more than 700 people, cell cultures, and animals—showed that elevated levels of CLU counteract inflammatory reactions between astrocytes and microglia and preserve synapses, the neuronal junctions vital to brain function.

Tracy Young-Pearse , co-author of the study, highlights its potential as a therapeutic tool complementary to already approved treatments, which could also benefit other brain diseases of aging with similar neuroinflammatory mechanisms. However, previous studies reveal that clusterin may also contribute to the progression of the disease.

In transgenic animal models of Alzheimer’s , genetic deletion of clusterin significantly reduced the formation of amyloid plaques, synaptic degeneration, and cognitive deficits in the early stages of the disease, although these effects disappeared in more advanced stages. This suggests that clusterin aggravates amyloid toxicity in the early stages, but loses relevance over time.

Brain distribution and genetic predispositions

In humans, this ambivalence also manifests itself: biomarkers such as clusterin concentration in cerebrospinal fluid (CSF) are associated with greater atrophy of the entorhinal cortex—one of the first regions affected in Alzheimer’s —especially in individuals with high levels of CSF amyloid.

Histopathological studies show that clusterin levels are higher in brain regions with greater amyloid accumulation, such as the frontal cortex and parahippocampus . However, in these areas, the ratio of clusterin to amyloid decreases, which could promote the formation of pathological deposits.

Furthermore, carriers of the APOE4 allele—a genetic risk factor for Alzheimer’s—have a higher accumulation of clusterin in synapses, which could enhance amyloid-related synaptic damage.

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(Featured image by Robina Weermeijer via Unsplash)

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First published in GACETA MEDICA. A third-party contributor translated and adapted the article from the original. In case of discrepancy, the original will prevail.

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