polysaccharides alleviate neuronal apoptosis induced by endoplasmic reticulum stress-activated PERK-ATF4-CHOP signaling in APP/PS1 mice.

in Journal of Alzheimer's disease : JAD by Yuanqin Cai, Xi Wang, Yang Xiang, Zhenning Wang, Qinghua Long, Chuhua Zeng

TLDR

  • CPPs improved learning and memory abilities in APP/PS1 mice by targeting the PERK-ATF4-CHOP signaling pathway and alleviating ERS, providing a potential therapeutic approach for AD treatment.

Abstract

Background(CPPs) shows neuroprotective potential in Alzheimer's disease (AD) and may reduce neuronal apoptosis by modulating endoplasmic reticulum stress (ERS).ObjectiveTo investigate the protective mechanisms of CPPs against neuronal apoptosis in APP/PS1 mice, focusing on the ERS response and the PERK-ATF4-CHOP signaling pathway.MethodsAPP/PS1 mice were orally administered CPPs at different doses. Their learning and memory abilities were evaluated using the Morris water maze (MWM). The integrity of hippocampal neurons and senile plaque deposition were assessed using histopathology, immunohistochemistry, and immunofluorescence. The expression of amyloid-β (Aβ) plaques secretase protein, ERS markers, and apoptosis-related proteins was assessed using western blot analyses. The affinity of the PERK-ATF4-CHOP pathway and CPPs was analyzed and assessed using molecular docking.ResultsMWM testing revealed that CPPs improved the learning and memory abilities of APP/PS1 mice. Histopathological examination confirmed that CPPs reduced hippocampal neuronal apoptosis. Immunohistochemistry and immunofluorescence analysis showed that CPPs decreased Aβ protein expression and ERS. Western blot analysis further confirmed that CPPs reduced the expression of proteins related to Aβ synthesis; downregulated the expression of glucose-regulated protein 78 (GRP78), PERK, ATF4, CHOP, and Bcl-2 associated X protein (Bax), while upregulating the expression of B-cell lymphoma 2 (Bcl-2).ConclusionsThis study demonstrates that CPPs exert neuroprotective effects by targeting the PERK-ATF4-CHOP signaling pathway and alleviating ERS, suggesting a novel approach and potential therapeutic agent for AD treatment.

Overview

  • The study investigates the protective mechanisms of CPPs against neuronal apoptosis in APP/PS1 mice, focusing on the ERS response and the PERK-ATF4-CHOP signaling pathway.
  • The study aims to evaluate the neuroprotective effects of CPPs on learning and memory abilities, hippocampal neuronal integrity, and senile plaque deposition in APP/PS1 mice.
  • The study hypothesizes that CPPs may reduce neuronal apoptosis by modulating ERS and the PERK-ATF4-CHOP signaling pathway, which could be a potential therapeutic approach for AD treatment.

Comparative Analysis & Findings

  • The study found that CPPs improved learning and memory abilities in APP/PS1 mice, and reduced hippocampal neuronal apoptosis and Aβ protein expression.
  • CPPs downregulated the expression of ERS markers, PERK, ATF4, CHOP, and Bax, while upregulating the expression of Bcl-2 and Bcl-2-associated X protein.
  • The study suggests that CPPs may target the PERK-ATF4-CHOP signaling pathway and alleviate ERS, providing a novel approach for AD treatment.

Implications and Future Directions

  • The study's findings highlight the potential therapeutic application of CPPs as a neuroprotective agent for AD treatment, and warrant further investigation into their mechanisms of action.
  • Future studies could explore the optimal doses and administration routes of CPPs for AD treatment, as well as investigate its effects on other AD-related pathologies.
  • Understanding the molecular mechanisms of CPPs' neuroprotective effects could lead to the development of novel therapeutic strategies for AD treatment.
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