Nasal Spray Targets Enzyme to Combat Alzheimer’s Cognitive Decline

Recent advancements in Alzheimer’s research have introduced an intriguing nasal spray aimed at combating cognitive decline, specifically targeting a key enzyme known as zDHHC.

This innovative approach shows promise for mitigating brain damage associated with Alzheimer’s disease, based on preliminary findings from animal studies.

A collaborative effort between researchers at Università Cattolica in Rome and Fondazione Policlinico Universitario Agostino Gemelli IRCCS has shed light on the fundamental mechanisms of Alzheimer’s pathology, highlighting crucial pathways for potential new treatments.

The Role of zDHHC in Alzheimer’s Disease

The concept of employing a nasal spray as a therapeutic intervention for Alzheimer’s has garnered increasing attention in the scientific community.

Researchers, led by Professors Claudio Grassi from the Department of Neuroscience and Salvatore Fusco from the University of Catania, propose that inhibiting the brain’s S-acyltransferase enzyme, commonly referred to as zDHHC, could reduce cognitive decline and neurodegeneration tied to the disease.

They discovered that the brains of people who succumbed to Alzheimer’s displayed elevated levels of S-acyltransferase, making it a promising target for novel pharmacological strategies.

A significant correlation was noted between heightened enzyme levels and decreased cognitive performance, prompting further investigation into therapies aimed at this enzyme.

A grant of €890,000 from the Ministry of Health’s 2023 PNRR initiative will support this pressing research endeavor.

Molecular Insights into Alzheimer’s

Understanding the mechanics behind Alzheimer’s progression reveals the disease’s complex interplay of proteins, particularly beta-amyloid and tau, which aggregate in the brain and disrupt normal function.

The biochemical process known as S-palmitoylation, mediated by enzymes like zDHHC, influences how these proteins behave.

Previous studies have illustrated that irregularities in the S-palmitoylation of synaptic proteins could be critical in the cognitive decline observed in metabolic disorders like type 2 diabetes.

This connection has led researchers to characterize Alzheimer’s as a form of type III diabetes due to the parallels with brain insulin resistance.

Recent findings suggest that the early stages of Alzheimer’s exhibit molecular changes that resemble brain insulin resistance.

This results in an increase in zDHHC7 enzyme levels, disrupting the S-palmitoylation of crucial proteins involved in cognitive function and contributing to beta-amyloid buildup.

The ramifications of this research are profound.

Inhibiting protein S-palmitoylation, through both pharmacological and genetic means, may effectively prevent the accumulation of deleterious proteins in neurons, as demonstrated in animal models of Alzheimer’s. Post-mortem analyses of brain samples from people who had Alzheimer’s revealed not only increased levels of zDHHC7 but also a negative correlation between cognitive performance and S-palmitoylation levels of critical proteins.

Future Directions and Innovations

In experimental studies involving genetically modified mice designed to model Alzheimer’s, researchers successfully inhibited the activity of the zDHHC enzyme using an experimental nasal spray agent called 2-bromopalmitate.

This approach not only halted the progression of neurodegeneration but also alleviated symptoms, improving the overall longevity of the subjects.

Currently, no drugs are available that can selectively inhibit zDHHC7.

Although 2-bromopalmitate shows promise, it lacks the precision needed for effective treatment.

However, with the backing of 2023 PNRR funding, researchers are exploring innovative strategies such as genetic patches that can specifically bind to zDHHC7 mRNA, thus obstructing its activation, alongside engineered proteins aimed at disrupting the enzyme’s functionality.

As this research unfolds, it heralds the potential for groundbreaking treatments that could profoundly change the lives of those affected by Alzheimer’s.

Study Details:

• Title: Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer’s disease
• Authors: Francesca Natale, Matteo Spinelli, Marco Rinaudo, Walter Gulisano, Ida Nifo Sarrapochiello, Giuseppe Aceto, Daniela Puzzo, Salvatore Fusco, Claudio Grassi
• Journal: Proceedings of the National Academy of Sciences
• Publication Date: 26 November 2024
• DOI: 10.1073/pnas.2402604121