Palmitoyl transferase zDHHCs: novel targets in Alzheimer’s disease

Background Growing evidence points to altered metabolic signals as a risk factor for Alzheimer’s disease (AD). The high fatty acid levels and brain insulin resistance (BIR) found in AD brains may impinge on protein S‐palmitoylation, which is a post‐translational modification critically involved in the regulation of neuronal protein localization and synaptic function. Our previous findings highlighted the critical role of aberrant palmitoylation in BIR‐dependent memory impairment (Spinelli et al., 2017). Method We analyzed both the expression of palmitoyl‐transferase enzymes (zDHHCs) in mouse AD brains and S‐palmitoylation levels of key proteins in human AD brains. We also tested the effect of chronic intranasal injection of the palmitoylation inhibitor 2‐bromopalmitate (2BP) on a large cohort of male and female 3xTg‐AD mice, starting from 3 months of age, by performing cognitive (novel object recognition and object displacement tests), electrophysiological (LTP), immunohistochemical (Abeta deposition) and molecular analyses (Abeta measurement by ELISA). Finally, we investigated the effects of lentiviral particles‐mediated zDHHC7 or zDHHC21 silencing in the hippocampus of 3xTg‐AD. Result We found increased levels of zDHHC7 and zDHHC21 in the hippocampus of 3xTg‐AD mice and aberrant palmitoylation of key enzymes triggering beta amyloid aggregation in human AD brains. 2BP delayed the onset of memory deficits in both male and female 3xTg‐AD mice. More importantly, 2BP significantly enhanced cognitive performances in 6‐, 9‐ and 12‐month‐old animals. Accordingly, electrophysiological analyses on hippocampal brain slices from 2BP‐treated 3xTg‐AD mice revealed greater long‐term potentiation at CA3‐CA1 synapses. In addition, both 2BP‐treated male and female mice showed lower Abeta deposition in hippocampus and a significant extension of lifespan. Finally, genetic inhibition of palmitoyl transferase zDHHC7 reverted the aberrant palmitoylation of proteins involved in synaptic plasticity and APP metabolism, and counteracted the onset of neurodegeneration and cognitive deficits in 3xTg‐AD mice. Conclusion This is the first preclinical study on the effect of 2BP treatment on AD‐related cognitive decline. Our data indicate that aberrant palmitoylation plays a critical role in the onset and progression of AD and unveil the potential druggable role of zDHHC enzymes in dementia‐related neurodegenerative disorders.