Researchers Identify Peptide That Counters Key Processes of Neurodegenerative Disorders

Alzheimer's disease and related neurodegenerative disorders are among medicine's most challenging conditions, progressively impairing memory, movement and independence. Now, researchers at the University of California San Diego School of Medicine have identified a naturally occurring peptide - a small protein fragment called catestatin (CST) - that may help counter several key processes driving neurodegeneration.

The researchers report that CST reduced the accumulation of abnormal proteins associated with neurodegenerative disease, including tau and amyloid, decreased inflammation in the brain, and improved cognitive and motor function in mouse models. The findings suggest that CST could provide the basis for a new peptide-based therapeutic strategy for Alzheimer's disease and related neurodegenerative disorders.

Neurodegenerative diseases involve multiple interconnected problems - including misfolded proteins, neuroinflammation and progressive dysfunction of brain cells. Our findings show that CST can act across several of these disease-associated pathways and shift the brain toward a healthier state. More broadly, the study suggests that peptide-based therapies may offer a new approach to treating complex neurodegenerative diseases."

Sushil K. Mahata, PhD, Study Senior Author and Professor, Medicine at, School of Medicine, University of California San Diego

Many experimental treatments for neurodegenerative disease are designed to target a single disease-associated protein or pathway. The new study suggests that CST may act more broadly, influencing multiple biological processes involved in neuronal function, inflammation and protein homeostasis. Such multi-pathway activity could be particularly valuable in complex disorders such as Alzheimer's disease, in which several disease mechanisms interact and evolve over time.

"One exciting aspect of our findings is that CST may do more than reduce the pathological features of neurodegeneration. We are also investigating whether CST can alter how the brain produces and uses energy, which may help neurons become more resilient to the cellular stress that occurs during neurodegeneration," said Suborno Jati, PhD, a postdoctoral scholar at UC San Diego School of Medicine and lead author of the study.

CST is derived from chromogranin A, a protein involved in cellular signaling as well as the storage and release of hormones and neurotransmitters. Previous research has also implicated CST in cardiovascular, metabolic and immune regulation, suggesting that the peptide participates in a broad network of physiological processes.

The researchers caution that the findings are preclinical. Additional studies will be needed to establish CST's safety, optimal dosing and effectiveness before the approach can be evaluated as a potential treatment in humans. Nevertheless, the results provide evidence supporting further development of CST and related molecules as potential therapeutics for neurodegenerative disease.

The study, published in the journal Molecular Therapy, was led by Sushil K. Mahata, PhD, of the UC San Diego Department of Medicine and VA San Diego Healthcare System; Suborno Jati, PhD; and Xu Chen, PhD, of the UC San Diego Department of Neurosciences. The research was supported in part by grants from the National Institutes of Health and the U.S. Department of Veterans Affairs.

Mahata is founder of CgA Therapeuticals, Inc. and co-founder of Siraj Therapeutics. Mahata and Jati are listed as co-inventors on intellectual property related to the findings.