A NEW potential treatment for Alzheimer’s disease may involve a nasal spray targeting a brain enzyme linked to cognitive decline.
Alzheimer’s disease, characterised by memory loss and cognitive impairment, is associated with the accumulation of proteins like beta-amyloid and tau in the brain. Researchers from Università Cattolica and Fondazione Policlinico Universitario A. Gemelli IRCCS have identified the enzyme S-acyltransferase (zDHHC) as a promising target for therapeutic intervention. This enzyme catalyses S-palmitoylation, a process affecting protein function, and is found in excess in the brains of Alzheimer’s patients. Elevated zDHHC7 levels were correlated with worse cognitive performance, highlighting its potential role in disease progression.
The researchers studied genetically modified mice exhibiting Alzheimer’s-like pathology, using the nasal-spray drug 2-bromopalmitate to inhibit zDHHC enzymes. This treatment reduced neurodegeneration, improved cognitive symptoms, and prolonged lifespan in the animals. Post-mortem analysis of human brain samples confirmed increased zDHHC7 and S-palmitoylated proteins in Alzheimer’s patients, alongside an inverse relationship between the levels of S-palmitoylated Beta-Secretase 1 and cognitive performance scores. The findings suggest that brain insulin resistance—common in Alzheimer’s and often dubbed “type III diabetes”—epigenetically drives zDHHC7 overexpression, contributing to cognitive decline. Pharmacological and genetic inhibition of S-palmitoylation effectively countered disease progression in animal models.
The study underscores the therapeutic potential of targeting zDHHC7 to mitigate Alzheimer’s symptoms and offers a foundation for future research. While current options, such as 2-bromopalmitate, lack precision, advanced strategies like engineered proteins and genetic patches are under exploration. These findings could lead to groundbreaking treatments that halt or reverse cognitive decline, providing new hope in clinical practice. Future efforts should focus on refining delivery methods and testing their safety and efficacy in humans, with the ultimate goal of translating these findings into viable therapies.
Reference
Natale F et al. Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of alzheimer’s disease. Proc Natl Acad Sci U S A. 2024;121(49):e2402604121.
