Recently approved Alzheimer's drugs offer a step forward for treating the disease, but new therapeutic strategies are needed to complement them and provide personalized therapeutic approaches. Mass General Brigham researchers have identified a potential strategy to protect against Alzheimer's disease by increasing the clusterin protein (CLU). Their results, published in Neuron , uncover the mechanism of how increased CLU protects the brain from amyloid plaques and loss of synapses, key aspects of the disease pathology, 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 Dennis J. Selkoe Endowed Chair in Neurology and Vice Chair of Neuroscience Research at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system. "Clusterin may also be beneficial for other brain diseases of aging given the mechanism we uncovered in our study."
Young-Pearse and the research team, with lead author Alexandra M. Lish of the Ann Romney Center for Neurologic Diseases, used several different models, including brain tissue from over 700 participants of the Religious Orders Study and Memory and Aging Projects, human brain cell models, and animal models to uncover CLU's molecular role. They found that reduction in CLU is associated with heightened inflammation. Increased CLU protected against these inflammatory interactions, particularly between brain cells called astrocytes and microglia. The findings consistently support the therapeutic hypothesis that increasing CLU in patients with amyloid plaques and tau tangles can prevent inflammatory signaling, protecting against neurodegeneration and cognitive decline. The researchers note that increasing CLU may also be beneficial for treating other age-related brain diseases, many of which share similar mechanisms of neuroinflammatory dysregulation.
The findings of CLU's neuroprotective effects have important implications for design and testing of new complementary therapeutic strategies for Alzheimer's disease, according to the researchers.
"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.
Authorship: In addition to Young-Pearse and Lish, Mass General Brigham authors include Elyssa Grogan, Courtney Benoit, Richard Pearse II, Sarah Heuer, Gwendolyn Orme, Paige Galle, Kellianne Alexander, Seeley Fancher, and Andrew Stern. Other authors include Tain Luquez, Giedre Milinkeviciute, Kim Green, Masashi Fujita, David Bennett, Nicholas Seyfried, Philip De Jager, and Vilas Menon.
Disclosures: None
Funding: This work was supported by the Alzheimer's Association (Zenith Award), and National Institutes of Health (U01AG061356, RF1AG057473, U01AG046152, R01AG066831, RF1AG072167, U01AG072572, R01NS117446, and R01AG055909).
Paper cited: Lish A, et al. "CLU alleviates Alzheimer's disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density" Neuron DOI: 10.1016/j.neuron.2025.03.034
