Search

Protein post-translational modifications (PTM) play a crucial role in the modulation of synaptic function and their alterations are involved in the onset and progression of neurodegenerative disorders. S-palmitoylation is a PTM catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases that affects both localization and activity of proteins regulating synaptic plasticity and amyloid-β (Aβ) metabolism. Here, we found significant increases of both zDHHC7 expression and protein S-palmitoylation in hippocampi of both 3×Tg-AD mice and post-mortem Alzheimer's disease (AD) patients. Chronic intranasal administration of the S-palmitoylation inhibitor 2-bromopalmitate counteracted synaptic plasticity and cognitive deficits, reduced the Aβ deposition in the hippocampus and extended the lifespan of both male and female 3×Tg-AD mice. Moreover, hippocampal silencing of zDHHC7 prevented the onset of cognitive deficits in the same experimental model. We also identified a FoxO1-mediated epigenetic mechanism inducing zDHHC7 expression, which was triggered by brain insulin resistance in 3×Tg-AD mice. Finally, in hippocampi of AD patients S-palmitoylation levels of Beta-Secretase 1 were associated with Aβ 1 to 42 load and they inversely correlated with Mini Mental State Examination scores. Our data reveal a key role of both zDHHC7 overexpression and protein hyperpalmitoylation in the onset and progression of AD-related alterations of synaptic plasticity and memory. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that activation of serotonin 5-HT 7 receptors (5-HT 7 R) reverses metabotropic glutamate receptor-mediated long term depression (mGluR-LTD) in the hippocampus of wild-type (WT) and Fmr1 Knockout (KO) mice, a model of Fragile X Syndrome (FXS) in which mGluR-LTD is abnormally enhanced. Here, we have investigated intracellular mechanisms underlying the effect of 5-HT 7 R activation using patch clamp on hippocampal slices. Furthermore, we have tested whether in vivo administration of LP-211, a selective 5-HT 7 R agonist, can rescue learning and behavior in Fmr1 KO mice. In the presence of an adenylate cyclase blocker, mGluR-LTD was slightly enhanced in WT and therefore the difference between mGluR-LTD in WT and Fmr1 KO slices was no longer present. Conversely, activation of adenylate cyclase by either forskolin or Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) completely reversed mGluR-LTD in WT and Fmr1 KO. 5-HT 7 R activation reversed mGluR-LTD in WT and corrected exaggerated mGluR-LTD in Fmr1 KO; this effect was abolished by blockade of either adenylate cyclase or protein kinase A (PKA). Exposure of hippocampal slices to LP-211 caused an increased phosphorylation of extracellular signal regulated kinase (ERK), an intracellular effector involved in mGluR-LTD, in WT mice. Conversely, this effect was barely detectable in Fmr1 KO mice, suggesting that 5-HT 7 R-mediated reversal of mGluR-LTD does not require ERK stimulation. Finally, an acute in vivo administration of LP-211 improved novel object recognition (NOR) performance in WT and Fmr1 KO mice and reduced stereotyped behavior in Fmr1 KO mice. Our results indicate that mGluR-LTD in WT and Fmr1 KO slices is bidirectionally modulated in conditions of either reduced or enhanced cAMP formation. Activation of 5-HT 7 receptors reverses mGluR-LTD by activation of the cAMP/PKA intracellular pathway. Importantly, a systemic administration of a 5-HT 7 R agonist to Fmr1 KO mice corrected learning deficits and repetitive behavior. We suggest that selective 5-HT 7 R agonists might become novel pharmacological tools for FXS therapy.