A research carried out by Università Cattolica in Rome and the Fondazione Policlinico Universitario Agostino Gemelli IRCCS has uncovered a big mechanism concerned in Alzheimer’s illness and recognized potential new therapeutic approaches.
A possible future therapy for Alzheimer’s illness may contain a nasal spray. Researchers from Università Cattolica and Fondazione Policlinico Universitario A. Gemelli IRCCS have recognized a solution to counteract cognitive decline and mind injury related to the illness by concentrating on the mind enzyme S-acyltransferase (zDHHC) with a nasal-spray drug. The research was led by Professor Claudio Grassi, Director of the Neuroscience Department, and Professor Salvatore Fusco, in collaboration with the University of Catania.
The researchers noticed that the autopsy brains of Alzheimer sufferers contained an extra of S-acyltransferase, which could possibly be a promising therapeutic goal of recent medicine. They additionally discovered that larger concentrations of this enzyme had been related to worse cognitive efficiency. Thanks to a €890,000 grant from the Ministry of Health’s 2023 PNRR name, new therapeutic approaches towards this enzyme might be explored.
Background
The growth of Alzheimer is pushed by alterations in sure proteins, together with beta-amyloid and tau, which combination and accumulate within the mind. These proteins’ features are regulated by a number of alerts and modifications, together with the attachment of a fatty acid molecule in a biochemical response referred to as “S-palmitoylation,” which is carried out by S-acyltransferase enzymes (zDHHC).
“In earlier research, we demonstrated that altered S-palmitoylation of synaptic proteins performs a crucial position in cognitive decline induced by metabolic ailments like kind 2 diabetes (Spinelli et al., Nature Communications) and that mind insulin resistance might affect the quantity of lively zDHHC enzymes within the mind,” Prof. Fusco explains. The authors additionally be aware a well-established link between insulin resistance and neurodegenerative ailments, a lot in order that Alzheimer’s is commonly referred to as kind III diabetes.
“In this new study, we showed that in the early stages of Alzheimer’s, 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.”
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 writer of the research Dr. Francesca Natale provides. Furthermore, in autopsy mind samples from Alzheimer’s sufferers, there are elevated ranges of zDHHC7 and S-palmitoylated proteins, with an inverse correlation between BACE1 S-palmitoylation ranges and cognitive upkeep scores on the Mini Mental State Examination.
In experiments carried out on genetically modified mice replicating Alzheimer’s dysfunction, researchers turned off zDHHC enzymes utilizing an experimental nasal-spray drug referred to as “2-bromopalmitate”. This method efficiently stopped neurodegeneration, diminished signs, and even prolonged the animals’ lifespan.
“Currently, no drugs can selectively block zDHHC7, and 2-bromopalmitate is not sufficiently precise”, Prof. Grassi says. However, due to the PNRR 2023 funding, new approaches—doubtlessly translatable to human therapies—might be examined, together with “genetic patches” (small ‘oligonucleotides’ that bind to the zDHHC7 enzyme’s RNA and forestall its maturation) or engineered proteins that may intervene with zDHHC enzyme exercise.”
Reference: “Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer’s disease” by Francesca Natale, Matteo Spinelli, Marco Rinaudo, Walter Gulisano, Ida Nifo Sarrapochiello, Giuseppe Aceto, Daniela Puzzo, Salvatore Fusco and Claudio Grassi, 26 November 2024, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2402604121
