Clinical Research Directory

Targeting zDHHC Enzymes to Counteract Alzheimer's Disease

Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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 Unpublished results showed aberrant protein S-palmitoylation in hippocampal tissues of both AD post-mortem brains and mouse experimental models of AD.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.

Official title: Developing New Therapeutic Strategies to Counteract Synaptic and Cognitive Deficits in Alzheimer's Disease by Targeting zDHHC Enzymes

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