Nasal spray drug could revolutionize Alzheimer’s treatment

A potential new treatment for Alzheimer’s disease may come in the form of a nasal spray. Researchers in Italy have discovered a method to counteract the cognitive decline and brain damage caused by Alzheimer’s by targeting a specific brain enzyme.

This breakthrough, led by scientists from the Università Cattolica and Fondazione Policlinico Universitario A. Gemelli IRCCS, could pave the way for innovative therapeutic strategies.

The team, in collaboration with the University of Catania, focused on inhibiting the enzyme S-acyltransferase (zDHHC7). This enzyme, which plays a role in protein modification, is found in excess in the brains of Alzheimer’s patients. Researchers believe this excess is linked to cognitive decline.

Their findings suggest that blocking this enzyme using a nasal spray could slow disease progression and reduce the accumulation of harmful proteins.

Thanks to a €890,000 grant from the Italian Ministry of Health’s 2023 PNRR initiative, the researchers will now explore advanced treatments targeting this enzyme. Their work represents a significant step forward in addressing a disease that affects millions globally.

Alzheimer’s is driven by the accumulation of misfolded proteins, including beta-amyloid and tau, in the brain. These proteins disrupt neural function and lead to progressive memory loss and cognitive impairment. Their behavior is regulated by post-translational modifications—chemical changes that occur after a protein is synthesized.

One such modification, S-palmitoylation, involves attaching a fatty acid molecule to proteins. This process is controlled by S-acyltransferase enzymes like zDHHC7.

“In prior studies, we found that increased S-palmitoylation of certain synaptic proteins plays a key role in cognitive decline associated with metabolic diseases such as type 2 diabetes,” explains Professor Salvatore Fusco, a lead researcher. “Brain insulin resistance, often seen in these conditions, impacts the activity of zDHHC enzymes.”

This connection between insulin resistance and neurodegenerative diseases has led some experts to describe Alzheimer’s as “type III diabetes.”

The new study builds on this link, showing that early-stage Alzheimer’s is associated with elevated levels of zDHHC7. This increase alters the S-palmitoylation of proteins critical for cognitive functions, exacerbating beta-amyloid accumulation and contributing to neuronal damage.

The researchers tested their hypothesis in genetically modified mice designed to mimic Alzheimer’s disease. By administering an experimental nasal spray containing 2-bromopalmitate, they were able to inhibit zDHHC enzymes. This intervention reduced beta-amyloid accumulation, slowed neurodegeneration, and even extended the animals’ lifespan.

“Our data demonstrate that both pharmacological and genetic inhibition of protein S-palmitoylation can counteract the accumulation of harmful proteins and delay cognitive decline,” explains Dr. Francesca Natale, the study’s lead author.

Post-mortem analyses of human brains further validated these findings. Patients with Alzheimer’s had significantly elevated levels of zDHHC7 and S-palmitoylated proteins. Notably, those with lower levels of a specific S-palmitoylated protein, BACE1, performed better on cognitive tests like the Mini-Mental State Examination (MMSE).

These results highlight zDHHC7 as a promising target for future therapies. However, current drugs like 2-bromopalmitate lack the specificity needed for clinical use.

Developing treatments that selectively target zDHHC7 is the next challenge. “To date, there are no drugs available that can specifically block zDHHC7,” says Professor Claudio Grassi, the study’s senior author. “Our team, with the support of PNRR funding, is working on novel approaches that could be translated to human therapies.”

One promising avenue involves genetic patches—short strands of nucleotides designed to bind to the RNA of zDHHC7 and prevent its activation. Another involves engineered proteins capable of directly interfering with the enzyme’s activity.

These strategies, if successful, could lead to the development of precise, effective treatments for Alzheimer’s. The use of a nasal spray for drug delivery offers additional advantages, including convenience and the ability to bypass the blood-brain barrier, which often limits the effectiveness of traditional medications.

While Alzheimer’s disease remains a complex and devastating condition, this research brings new hope. By targeting the molecular mechanisms underlying the disease, scientists are not only advancing our understanding but also opening doors to transformative therapies.

If successful, these approaches could change the trajectory of Alzheimer’s treatment, offering patients and their families a brighter future.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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