Cattle Encephalon Glycoside and Ignotin Ameliorate Palmitoylation of PSD-95 and Enhance Expression of Synaptic Proteins in the Frontal Cortex of a APPswe/PS1dE9 Mouse Model of Alzheimer's Disease

Background: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer's disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-beta (A beta) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence A beta deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. Objective: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 (PSD-95) palmitoylation, A beta pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. Methods: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. Results: CEGI treatment in APP/PS1 mice significantly reduced A beta deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between A beta expression and PSD-95 palmitoylation in APP/PS1 mice. Conclusion: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment.