Researchers from Università Cattolica and Fondazione Policlinico Universitario A. Gemelli IRCCS in Italy are developing an innovative treatment aimed at slowing the cognitive decline and brain damage synonymous with the disease. This promising therapy targets a specific brain enzyme, S-acyltransferase (zDHHC), which could transform the way we approach Alzheimer’s care.
The Research and Discovery
Led by Professors Claudio Grassi and Salvatore Fusco, with support from the University of Catania, the team identified zDHHC as a critical enzyme in Alzheimer’s pathology. Post-mortem studies revealed that Alzheimer’s patients exhibited elevated levels of zDHHC, which is associated with worse cognitive performance. By targeting this enzyme, the researchers believe they can halt or even reverse key aspects of the disease.
To test their theory, the researchers used an experimental nasal spray containing 2-bromopalmitate in animal models of Alzheimer’s. The results were groundbreaking: the spray successfully inhibited zDHHC activity, slowed cognitive decline, reduced harmful protein accumulation, and even extended the lifespan of the test subjects.
How It Works
Alzheimer’s is driven by the accumulation of misfolded proteins, such as beta-amyloid and tau, which disrupt normal brain function. These proteins undergo chemical modifications like S-palmitoylation, where fatty acids attach to proteins, mediated by enzymes like zDHHC. When this process is disrupted, it exacerbates beta-amyloid accumulation, leading to neurodegeneration.
The nasal spray inhibits zDHHC, preventing the harmful protein buildup and preserving cognitive functions. While the experimental drug 2-bromopalmitate is not yet precise enough for human use, the research underscores the therapeutic potential of targeting this enzyme.
Results of the Study
In addition to animal studies, post-mortem analyses of human brains provided further validation. Alzheimer’s patients exhibited higher levels of zDHHC and S-palmitoylated proteins. Interestingly, patients with lower levels of certain S-palmitoylated proteins, such as BACE1, scored better on cognitive tests like the Mini-Mental State Examination (MMSE).
Dr. Francesca Natale, the lead author of the study, explained, “Our findings demonstrate that both pharmacological and genetic inhibition of protein S-palmitoylation can counteract the accumulation of harmful proteins and delay cognitive decline.”
Next Step
The researchers have received a €890,000 grant from the Italian Ministry of Health’s 2023 PNRR initiative to refine their approach. Future treatments could include genetic patches—short strands of nucleotides designed to block zDHHC’s activity—or engineered proteins to inhibit the enzyme.
The nasal spray delivery system offers distinct advantages, such as bypassing the blood-brain barrier, a significant obstacle in traditional Alzheimer’s therapies.
“While 2-bromopalmitate is not sufficiently precise, we are optimistic that new approaches funded by the PNRR will yield therapies translatable to humans,” said Professor Grassi.
What This Means for Alzheimer’s Treatment
If successful, these therapies could revolutionize Alzheimer’s treatment by addressing the disease at a molecular level. The nasal spray offers a non-invasive, accessible, and potentially transformative option for patients and caregivers.
This research also highlights a deeper understanding of Alzheimer’s, often referred to as “type III diabetes,” due to its link with insulin resistance. By targeting zDHHC and its role in metabolic and neurodegenerative pathways, scientists are bridging gaps between previously separate fields of study.
As researchers advance toward clinical trials, the promise of this nasal spray is clear: it could redefine how we treat and understand Alzheimer’s, bringing hope to millions affected by the disease worldwide.
