Targeting zDHHC Enzymes to Counteract Alzheimer's Disease

NCT06677632 | Not Yet Recruiting

• 1 other identifier: 6858
• Study Type: observational
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

Alzheimer's disease (AD) is a growing problem for aging populations worldwide and represents one of the most demanding challenges for biomedical and pharmacological research. All therapeutic attempts made so far based on current knowledge have proven scarcely effective, probably because the molecular mechanisms underlying the onset and progression of the disease remain poorly understood. Neuroinflammation and alteration of brain insulin signaling have been demonstrated to induce an AD-like phenotype and accelerate neurodegeneration in the hippocampus and neocortex of experimental models of AD. An increasing number of studies have shown the role of palmitoylated proteins in the regulation of synaptic plasticity and neuronal functions. Aberrant protein S-palmitoylation plays a pivotal role in brain insulin resistance (BIR)-dependent cognitive decline. Moreover, protein S-palmitoylation can target immune signaling pathways (e.g., STING, NOD1/2, JAK-STAT, T cell receptor signaling) and modulate inflammatory responses. Accordingly, S-palmitoylation has been shown to regulate localization and activity of several enzymes involved in cytokine receptor-mediated signaling and neuroinflammation. Unpublished results showed aberrant protein S-palmitoylation in hippocampal tissues of both AD post-mortem brains and mouse experimental models of AD. Preliminary data reveal a key role of palmitoyltransferase enzymes (zDHHCs), which catalyze the S-palmitoylation of substrate proteins, in the development of neurodegeneration and cognitive deficits, suggesting that counteracting aberrant protein S-palmitoylation can be a novel therapeutic strategy for AD. Nevertheless, to date, therapeutic approaches targeting protein S-palmitoylation have not yet been attempted in AD and there are currently no available drugs specifically targeting zDHHCs. The goal of this study is to develop novel therapeutic strategies targeting zDHHC enzymes to counteract S-palmitoylation-dependent synaptic and cognitive deficits in AD. Additionally, new biotechnological approaches aimed at inhibiting zDHHCs and their targets will be set up to expand the range of tools capable of interfering with altered protein S-palmitoylation in AD. To this end, a combination of different in vitro and in vivo techniques (electrophysiology, molecular biology, behavioral tests, microscopy studies) will be used in both animal and human models of AD, concurrent with innovative biotechnological strategies.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (2)

• Differences in zDHHC mRNA and protein expression levels between Alzheimer's disease (AD) models and control samples

  Levels of zDHHC enzymes will be quantified in AD models and controls to measure potential differences. Real-Time PCR will be used to assess mRNA expression, while Western blotting will measure protein levels, providing detailed profiles of zDHHC expression.

  Year 1

• Change in AD-associated deficits following zDHHC7 downregulation

  Measurable changes in AD-associated deficits will be assessed after zDHHC7 downregulation, with a focus on alterations in cellular or molecular markers relevant to Alzheimer's pathology.

  Year 1

Secondary Outcomes (1)

• Decrease in zDHHC enzyme expression in human experimental models of Alzheimer's disease

  Year 2

Study Arms (1)

Alzheimer's disease patients

TO DETERMINE THE EXPRESSION OF zDHHC ENZYMES AND CHANGES OF PROTEIN S- PALMITOYLATION IN THE hiPSC-DERIVED NEURONS AND BRAIN ORGANOIDS OBTAINED FROM AD PATIENTS

Other: Palmitoylation Enzyme Expression Profiling Study

Interventions

Palmitoylation Enzyme Expression Profiling Study OTHER

The expression of 23 zDHHC enzymes will be studied in human post-mortem hippocampi of AD patients and controls that have already been collected from UK brain biobanks. zDHHC enzymes will be analyzed at both mRNA and protein levels by Real Time PCR and Western blotting techniques, respectively

Alzheimer's disease patients

Eligibility Criteria

• Age: 18 Years - 80 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population will be drawn from adults receiving care at Clinica della Memoria at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome, Italy

You may qualify if:

• Clinical diagnosis of Alzheimer's Disease
• Age between 18 and 80 years
• Signed informed consent obtained

You may not qualify if:

• Patients suffering from other neurological diseases;
• Patients with coagulation disorders or in treatment with anticoagulant drugs;
• Patients suffering from dermatological diseases and connective tissue diseases;
• Patients suffering from other organic, psychiatric diseases or laboratory abnormalities could preclude participation or invalidate the study results;
• Inability to give informed consent.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

Fondazione Policlinico Universitario A. Gemelli IRCCS

Roma, 00168, Italy

Location

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Claudio Grassi

  Fondazione Policlinico Universitario A. Gemelli, IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Claudio Grassi

CONTACT

+390630154966; claudio.grassi@policlinicogemelli.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2024
• First Posted: November 7, 2024
• Study Start: November 11, 2024
• Primary Completion: August 31, 2025
• Study Completion (Estimated): August 31, 2026
• Last Updated: November 7, 2024

Record last verified: 2024-07

Locations

IT (1)