Summary: The researchers identified a promising drug candidate, DDL-357, which improves memory in Alzheimer’s mouse models by increasing the levels of a protective cerebral protein called clusterine (Clu). It helps prevent the accumulation of toxic amyloid plates and tau protein, both key motors in Alzheimer’s disease.
In mice, the DDL-357 has reduced phospho-Tau levels, improved mitochondrial function and improvement in cognitive performance in labyrinth tests. Although always in the early stages, this candidate drug can operate alongside existing treatments and could possibly be used for other neurodegenerative diseases such as Parkinson and SLA.
Key facts:
- Targeted protein: The DDL-357 stimulates the secreted cluster (SCLU), which protects against the accumulation of toxic brain.
- Memory gains: The treated Alzheimer’s models have shown improvement in memory and cognitive function.
- Broader potential: The drug can help treatment for other diseases such as ALS and Parkinson.
Source: UCLA
While researchers are working to improve the treatment of Alzheimer’s disease, new research from the UCLA Health has identified a candidate drug that reduces the levels of a toxic form of a protein in the brain caused by the disease and improved memory in mice by stimulating the production of a protective protein.
In a study published in the Nature newspaper NPJ Drug Discovery, UCLA health researchers have targeted protein cluster (Clu), which is crucial to preventing the accumulation of amyloid -bêta plates and tau proteins that disrupt communication between brain cells and cause memory disorders – a characteristic symptom of Alzheimer’s disease.
More than a decade ago, a variant of the gene coded in clustering was identified as the third strongest genetic risk factor in Alzheimer’s disease with late early. It has recently been reported that an increase in Clu proteins could ensure protection against Alzheimer’s disease and cognitive decline.
The UCLA health researchers led by Varghese John identified a small candidate molecule, DDL-357, which increased the concentrations of secreted clusterine (SCLU) in the models of Alzheimer’s mouse, resulting in a reduction in the toxic phospho-cable protein and the improvement of the mitochondrial function, both associated with the progress of the disease.
DDL-357 has also improved the memory of the mice treated in cognitive labyrinth tests.
“Our results open the door to the development of new treatments that target not only the underlying causes of Alzheimer’s disease, but also to restore the lost cognitive function – something that existing therapies must still achieve,” said John, professor of neurology and director of the drug discovery laboratory (DDL) at Mary S. Easton Center for Alzheimer and Care UCLA.
“While the drug candidate is still in preclinical test and far from human trials, the first results suggest that this could work in concert with existing Alzheimer’s disease and can also be effective in the treatment of other neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis,” said John.
The drug is one of the last researchers that John and his colleagues in health researchers from UCLA at the Drug Discovery Laboratory have identified as potential candidates for development to treat Alzheimer’s disease.
A molecule, known as DDL-920, was noted to restore cognitive function in alzheimer’s models by jumping the brain’s memory circuits, specifically targeting the gamma oscillations that orchestrate the circuits for cognition and working memory.
Another study published in April revealed that the DDL-218 molecule has worked to increase mouse brain levels of another protection protein, Sirtuin 1, which is lower in people who carry the E4 apolipoprotein, a genetic variant of apolipoprotein, which gives the greatest risk of late Alzheimer’s disease.
These potential candidates on drugs offer an opportunity for testing new therapies complementary to Alzheimer’s disease.
About this neuropharmacology and news of research on Alzheimer’s disease
Author: Will Houston
Source: UCLA
Contact: Will Houston – UCLA
Picture: The image is credited with Neuroscience News
Original search: Open access.
“The discovery of a clusterin amplifier secreted by a small molecule that improves memory in mice of Alzheimer’s disease” by Varghese John et al. Discovery of NPJ drugs
Abstract
Discovery of an enclosure amplifier secreted by a small molecule that improves memory in mice of Alzheimer’s disease
Despite substantial efforts to research and discovery of drugs, Alzheimer’s (AD) remains the sixth cause of death in the United States, highlighting the urgent need for new therapeutic targets.
A mutation in the clusterin gene (Clu) which hinders the expression of the isoform secreted by the cyto-protection of the clusterine (SCLU) which affects the aggregation and clearance of two key proteins involved in the MA, Aβ and TAU, is the third most significant genetic risk factor for the end.
Here, we present the results of our drug discovery program to identify small molecules that improve sclu levels and assess their impact on the pathology and cognition of MA in a MURIN MA model.
A high-speed screening campaign has identified two classes of epigenetic modulators that increase sclu levels with subsequent medicinal chemistry efforts leading to the bromodoman and the extra-terminal inhibitor (BET) of new chemical entities (NCE) with improved power, medicine-type properties and oral brain bioavail.
The main candidate NCE, DDL-357, increased the brain sclu in the MURIN APOE4TR-5XFAD model in a sub-chronic study. In a chronic monitoring study in the Murine 3XTG-AD model, DDL-357 reduced phospho-cars in the brain and has caused improvements in performance and mouse memory in the barn labyrinth tests.
The proteomic analysis of the brain fabric of the two models of MA revealed changes in the proteins involved in the mitochondrial function and synaptic plasticity.
These results reveal the potential of improving the sclu as the objective of therapeutic development in the MA and support the continuous development of the main preclinical candidate.
