Nasal Spray for Alzheimer’s: Promising New Treatment

A nasal spray may be used in the future to treat Alzheimer’s disease. Researchers from Università Cattolica and Fondazione Policlinico Universitario A. Gemelli IRCCS revealed that by suppressing the brain enzyme S-acyltransferase (zDHHC) with a nasal spray medication, they can prevent cognitive loss and brain damage associated with the disease. Professor Claudio Grassi, Director of the Neuroscience Department, and Professor Salvatore Fusco directed the study, which was conducted in partnership with the University of Catania.

The researchers discovered that the post-mortem brains of Alzheimer’s patients showed an overabundance of S-acyltransferase, which could be a promising therapeutic target for future treatments. They also discovered that higher levels of this enzyme were connected with poor cognitive performance. With a €890,000 funding from the Ministry of Health’s 2023 PNRR call, novel treatment approaches against this enzyme will be investigated.

Background

Alzheimer’s disease is caused by changes in specific proteins, such as beta-amyloid and tau, which cluster and accumulate in the brain. Multiple signals and changes regulate the activity of these proteins, including the attachment of a fatty acid molecule in a biochemical reaction known as “S-palmitoylation” done by S-acyltransferase enzymes (zDHHC).

“In previous studies, we demonstrated that altered S-palmitoylation of synaptic proteins plays a critical role in cognitive decline induced by metabolic diseases like type 2 diabetes (Spinelli et al., Nature Communications) and that brain insulin resistance may impact the amount of active zDHHC enzymes in the brain,” Prof. Fusco explains. The authors also note a well-established link between insulin resistance and neurodegenerative diseases, so much so that Alzheimer’s is often called type III diabetes.

In this new study, we showed that in the early stages of Alzheimer, molecular changes resembling a scenario of brain insulin resistance cause an increase of zDHHC7 enzyme levels and alter the S-palmitoylation of key proteins involved in cognitive functions and beta-amyloid accumulation.”

Salvatore Fusco, Professor, Universita Cattolica del Sacro Cuore

Toward new treatment options

“Our findings show that in animal models of Alzheimer’s disease, both pharmacological and genetic inhibition of protein S-palmitoylation can counteract the accumulation of harmful proteins in neurons and delay the onset and progression of cognitive decline”, the lead author of the study Dr. Francesca Natale adds. Furthermore, in post-mortem brain samples from Alzheimer’s patients, there are elevated levels of zDHHC7 and S-palmitoylated proteins, with an inverse correlation between BACE1 S-palmitoylation levels and cognitive maintenance scores on the Mini Mental State Examination.

In trials on genetically modified mice mimicking Alzheimer’s disease, researchers shut off zDHHC enzymes with an experimental nasal-spray medication dubbed “2-bromopalmitate”. This technique effectively prevented neurodegeneration, reduced symptoms, and even increased the animals’ lifetime.

“Currently, no drugs can selectively block zDHHC7, and 2-bromopalmitate is not sufficiently precise”, Prof. Grassi says. However, thanks to the PNRR 2023 funding, new approaches-;potentially translatable to human therapies-;will be tested, including “genetic patches” (small ‘oligonucleotides’ that bind to the zDHHC7 enzyme’s RNA and prevent its maturation) or engineered proteins that can interfere with zDHHC enzyme activity.”