As researchers work to improve treatment of Alzheimer’s disease, new research by UCLA Health identified a candidate drug that reduces levels of a toxic form of a protein in the brain caused by the disease and improved memory in mice by boosting production of a protective protein.
In a study published in the Nature journal npj Drug Discovery, UCLA Health researchers targeted the protein clusterin (CLU), which is crucial in preventing the build-up of amyloid-beta plaques and tau proteins that that disrupt communication between brain cells and lead to memory impairment — a hallmark symptom of Alzheimer’s disease.
More than a decade ago, a variant of the gene that encodes clusterin was identified as the third strongest genetic risk factor for late-onset Alzheimer’s disease. It was recently reported that increased CLU protein could provide protection against Alzheimer’s disease and cognitive decline. UCLA Health researchers led by Varghese John identified a candidate small molecule, DDL-357, that increased concentrations of secreted clusterin (sCLU) in Alzheimer’s mouse models, resulting in a reduction of the toxic protein phospho-tau and improvement of mitochondrial function, both associated with progression of the disease. DDL-357 also improved the memory of treated mice in maze-based cognitive tests.
“Our findings open the door to the development of new treatments that not only target the underlying causes of Alzheimer’s disease but also restore lost cognitive function – something that existing therapies have yet to achieve,” said John, a professor of neurology and director of the Drug Discovery Laboratory (DDL) at the Mary S. Easton Center for Alzheimer's Disease Research and Care at UCLA.
“While the drug candidate is still in pre-clinical testing and far from human trials, initial results suggest it could work in concert with existing Alzheimer’s disease treatments and may also be effective in treating other neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis”, John said.
The drug is one of the latest that John and fellow UCLA Health researchers at the Drug Discovery Laboratory have identified as potential candidates for development to treat Alzheimer’s disease. One molecule, known as DDL-920, was found to restore cognitive function in Alzheimer’s model mice by jumpstarting the brain's memory circuitry, specifically targeting gamma oscillations that orchestrate circuits for cognition and working memory. Another study published in April found the molecule DDL-218 worked to increase levels in mouse brain of another protective protein, sirtuin 1, that is lower in people who carry apolipoprotein E4, a genetic variant of apolipoprotein, that confers the greatest risk for late-onset Alzheimer’s disease. These potential drug candidates provide an opportunity for the testing of new complimentary therapies for Alzheimer’s disease.
npj Drug Discovery
Randomized controlled/clinical trial
Animals
Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer’s disease mice
2-May-2025