Italian researchers have discovered that inhibiting the brain enzyme S-acyltransferase (zDHHC7) via a nasal spray could potentially revolutionize Alzheimer's treatment by counteracting cognitive decline and brain damage. The team, in collaboration with the University of Catania, is focusing on blocking this enzyme, which is found in excess in the brains of Alzheimer’s patients and is believed to be linked to cognitive decline.
Targeting zDHHC7 for Alzheimer's Treatment
The research builds upon previous findings that increased S-palmitoylation of synaptic proteins plays a key role in cognitive decline, often associated with metabolic diseases like type 2 diabetes. Professor Salvatore Fusco noted the connection between insulin resistance and neurodegenerative diseases, leading some experts to describe Alzheimer’s as “type III diabetes.” The new study indicates that early-stage Alzheimer’s is associated with elevated levels of zDHHC7, altering the S-palmitoylation of proteins critical for cognitive functions, which exacerbates beta-amyloid accumulation and contributes to neuronal damage.
Experimental Results in Mice
To test their hypothesis, the researchers administered an experimental nasal spray containing 2-bromopalmitate to genetically modified mice designed to mimic Alzheimer’s disease. The intervention successfully inhibited zDHHC enzymes, reducing beta-amyloid accumulation, slowing neurodegeneration, and even extending the animals’ lifespan. Dr. Francesca Natale, the study’s lead author, explained that both pharmacological and genetic inhibition of protein S-palmitoylation can counteract the accumulation of harmful proteins and delay cognitive decline.
Validation in Human Brains
Post-mortem analyses of human brains further validated these findings, revealing that Alzheimer’s patients had significantly elevated levels of zDHHC7 and S-palmitoylated proteins. Notably, individuals with lower levels of a specific S-palmitoylated protein, BACE1, demonstrated better performance on cognitive tests such as the Mini-Mental State Examination (MMSE). These results underscore zDHHC7 as a promising target for future therapies.
The Road Ahead: Developing Specific Therapies
Despite the promising results, current drugs like 2-bromopalmitate lack the specificity required for clinical use. Professor Claudio Grassi, the study’s senior author, emphasized the need for treatments that selectively target zDHHC7. With the support of an €890,000 grant from the Italian Ministry of Health’s 2023 PNRR initiative, the team is working on innovative approaches, including genetic patches designed to bind to the RNA of zDHHC7 and engineered proteins capable of directly interfering with the enzyme’s activity. The use of a nasal spray for drug delivery offers advantages such as convenience and the ability to bypass the blood-brain barrier, potentially enhancing the effectiveness of the treatment.
