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Increase of Clusterin Protein Could Protect from Alzheimer’s Disease
In a new study published in Neuron titled “CLU alleviates Alzheimer’s disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density,” researchers from Mass General Brigham have identified a potential strategy to protect
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In a new study published in Neuron titled “CLU alleviates Alzheimer’s disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density,” researchers from Mass General Brigham have identified a potential strategy to protect against Alzheimer’s disease (AD) by increasing the clusterin (CLU) protein, a molecular chaperone that binds misfolded proteins.
Their results uncover the mechanism of how increased CLU protects the brain from amyloid plaques and loss of synapses, while also identifying which individuals are most likely to respond based on their genetics.
“Increasing clusterin has the potential to prevent cognitive decline in a way that is different than and complementary to anti-amyloid therapies to promote brain resilience,” said Tracy Young-Pearse, PhD, the vice chair of neuroscience research at Brigham and corresponding author of the study. “Clusterin may also be beneficial for other brain diseases of aging, given the mechanism we uncovered in our study.”
CLU facilitates the clearance of misfolded proteins through receptor-mediated endocytosis. In Alzheimer’s, CLU localizes to amyloid plaques and modulates removal, supporting a neuroprotective role.
While prior studies have advanced understanding of CLU biology, they have largely relied on mouse models or investigated CLU’s role outside the brain. Employing physiologically relevant systems in which CLU is expressed in human cells is important for determining the role of CLU in Alzheimer’s risk.
To elucidate CLU’s mechanistic role in Alzheimer’s, the researchers leveraged several different models, including human brain cell models, animal models, and brain tissue from over 700 participants of the Religious Orders Study and Memory and Aging Projects, a longitudinal, epidemiologic clinical-pathological study of memory, motor, and functional problems in individuals aged 65 years and older from across the United States. Results from multi-omic, post-mortem studies of human brain tissue showed that CLU expression is higher in AD brain tissue.
The authors found that reduction of CLU produced from astrocytes, glial cells in the brain and spinal cord, caused microglia, immune cells of the central nervous system, to modulate extracellular apolipoprotein E (APOE) and phosphorylated tau, two proteins associated with neurodegenerative disease. The study also demonstrated that CLU Alzheimer’s-risk alleles are associated with reduced CLU protein and heightened inflammatory profiles.
“As amyloid accumulates in the brain, some individuals can mount a protective response by efficiently upregulating CLU, which helps preserve synapses and prevent cognitive decline. In others, this response is impaired, leading to insufficient CLU production, heightened inflammation, and progression toward Alzheimer’s disease,” said Young-Pearse.
Taken together, the results establish a mechanistic link between Alzheimer’s genetic risk factors, astrocyte reactivity, and microglia-mediated effects on synaptic integrity to produce the protective effect caused by CLU upregulation.
The findings of CLU’s neuroprotective effects have important implications for the design and testing of new complementary therapeutic strategies for Alzheimer’s disease. In addition, increasing CLU may be beneficial for treating other age-related brain diseases, many of which share similar mechanisms of neuroinflammatory dysregulation.