Summary: Researchers have identified a promising drug candidate, DDL-357, that improves memory in Alzheimer’s mouse models by increasing levels of a protective brain protein called clusterin (CLU). CLU helps prevent the buildup of toxic amyloid-beta plaques and tau proteins, both key drivers of Alzheimer’s disease.
In mice, DDL-357 reduced levels of phospho-tau, improved mitochondrial function, and enhanced cognitive performance in maze tests. Though still in early stages, this candidate drug may work alongside existing treatments and could eventually be used for other neurodegenerative diseases like Parkinson’s and ALS.
Key Facts:
- Targeted Protein: DDL-357 boosts secreted clusterin (sCLU), which protects against toxic brain buildup.
- Memory Gains: Treated Alzheimer’s model mice showed improved memory and cognitive function.
- Broader Potential: The drug may aid treatment for other diseases like ALS and Parkinson’s.
Source: UCLA
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.
Credit: Neuroscience News
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.
About this Neuropharmacology and Alzheimer’s disease research news
Author: Will Houston
Source: UCLA
Contact: Will Houston – UCLA
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer’s disease mice” by Varghese John et al. npj Drug Discovery
Abstract
Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer’s disease mice
Despite substantial research and drug discovery efforts, Alzheimer’s Disease (AD) remains the sixth leading cause of death in the United States, underscoring the urgent need for novel therapeutic targets.
A mutation in the clusterin (CLU) gene that hinders expression of the cyto-protective secreted isoform of clusterin (sCLU) that affects the aggregation and clearance of two key proteins implicated in AD, Aβ and tau, is the third most significant genetic risk factor for late-onset AD.
Here, we present findings from our drug discovery program to identify small molecules that enhance sCLU levels and assess their impact on AD pathology and cognition in a murine model of AD.
A high-throughput screening campaign identified two classes of epigenetic modulators that increase sCLU levels with subsequent medicinal chemistry efforts leading to bromodomain and extra-terminal (BET) inhibitor new chemical entities (NCEs) with enhanced potency, drug-like properties, and oral brain bioavailability.
The lead candidate NCE, DDL-357, increased brain sCLU in the murine ApoE4TR-5XFAD model of AD in a subchronic study. In a follow-up chronic study in the murine 3xTg-AD model, DDL-357 reduced phospho-tau in brain and led to improvements in mouse performance and memory in the Barnes maze testing paradigm.
Proteomic analysis of brain tissue from both AD models revealed changes in proteins involved in mitochondrial function and synaptic plasticity.
These findings reveal the potential of sCLU enhancement as a target for therapeutic development in AD and support the continued development of the preclinical lead candidate.
