A La Jolla research team has identified a small protein fragment that reduced hallmarks of Alzheimer's disease in mice, clearing toxic proteins and improving memory and movement.

The peptide, called catestatin, or CST, acted on multiple disease pathways at once, according to a UC San Diego School of Medicine announcement published Monday, Sept. 21. The study appeared the same day in the journal Molecular Therapy.

In two separate mouse models, CST lowered levels of tau and amyloid, the abnormal proteins that accumulate in the brains of Alzheimer's patients. It also reduced brain inflammation and improved cognitive and motor function, the university said.

Most experimental Alzheimer's treatments target a single protein or pathway. CST appears to work differently, influencing several biological processes tied to neuronal function, inflammation and protein balance.

"Our findings show that CST can act across several of these disease-associated pathways and shift the brain toward a healthier state," said Sushil K. Mahata, professor of medicine at UC San Diego School of Medicine and research physiologist at the VA San Diego Healthcare System.

Mahata served as senior author. Lead author Suborno Jati, a postdoctoral scholar at UC San Diego, said the team is also investigating whether CST can change how the brain produces and uses energy, potentially helping neurons withstand cellular stress.

CST is derived from chromogranin A, a protein involved in cellular signaling and the storage and release of hormones and neurotransmitters. Earlier research has linked CST to cardiovascular, metabolic and immune regulation, suggesting it plays a role across many body systems.

The study found that brains affected by Alzheimer's had markedly lower CST levels and higher levels of a related peptide called pancreastatin. That imbalance also appeared in brain tissue from patients with two other neurodegenerative conditions, corticobasal degeneration and progressive supranuclear palsy.

Mechanistically, CST reduced epinephrine levels in the mouse models and suppressed overactivation of Protein Kinase A (PKA), an enzyme involved in stress signaling. The researchers said this reveals a connection between CST deficiency, stress hormones and the progression of tau-related brain damage.

The research was funded in part by 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. He and Jati are listed as co-inventors on intellectual property related to the findings.

The findings remain preclinical. The university said additional studies are needed to establish CST's safety, optimal dosing and effectiveness before the approach can be tested in humans. No clinical trial date has been announced.