Targeting zDHHC Enzymes to Counteract Alzheimer's Disease

S-palmitoylation is a protein post-translational modification involving the attachment of a palmitic acid molecule to cysteine residues. This modification influences protein trafficking toward cellular membranes and is finely regulated by a class of enzymes named zinc finger DHHC domain containing (zDHHC) S-acyltransferases. Proteins critically involved in Alzheimer's disease (AD), such as APP and BACE1, are targets of S-palmitoylation. Higher levels of S-palmitoylated proteins have been found in both post-mortem brain samples and brain organoids derived from induced pluripotent stem cells (hiPSCs) obtained from AD patients. Notably, both neurons and brain organoids derived from human AD hiPSCs exhibited molecular, morphological, and functional alterations reminiscent of AD. Intranasal administration of the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly counteracted LTP and memory deficits in 3×Tg-AD mice, extended lifespan, and decreased Aß deposition. Higher levels of zDHHC7 and zDHHC21 were also found in the hippocampus of 3×Tg-AD mice. Silencing of zDHHC7 in the hippocampus of 3×Tg-AD mice prevented cognitive deficits and Aß accumulation, along with counteracting palmitoylation of proteins critically involved in neuronal function. This confirms that modulation of zDHHC activity may be exploited for AD treatment. The idea underlying this project is based on the assumption that zDHHC enzymes and alteration of protein S-palmitoylation play a key role in the onset and progression of AD. Dysregulated zDHHC activity and aberrant S-palmitoylation of neuronal proteins critically involved in the regulation of brain plasticity, neuroinflammation, and Aß metabolism can affect synaptic function, protein homeostasis, and mitochondrial activity, leading to the development of neurodegeneration and cognitive deficits. A druggable target, zDHHC7, has been identified to test the efficacy of novel therapeutic approaches. This study aims to validate a new strategy targeting zDHHC enzymes in human experimental models of AD. Human models will allow an understanding of the translation potential of these approaches to human disease, to be validated in subsequent clinical trials whose implementation exceeds the duration of the present project.