Calcium-Sensing Receptor Mediates β-Amyloid-Induced Synaptic Formation Impairment and Cognitive Deficits via Regulation of Cytosolic Phospholipase A2/Prostaglandin E2 Metabolic Pathway.

Chenxi Feng,Qinwen Wang,Wei Cui,Jia Wang,Yanfei Ding,Yanzi Cao,Yunxiang Ling,Xiaoming Bao,Ling Shan,Shujun Xu

doi:10.3389/fnagi.2020.00144

Abstract

Calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCRs). Soluble β-amyloid peptide (Aβ) is one of the orthosteric modulators of CaSR, while, the role and underlying mechanism of CaSR in cognitive decline in Alzheimer’s disease (AD) is unclear. In this study, molecular technology such as live-cell imaging combined with behavioral tests were used to explore the role and the underlying mechanism of CaSR in the cognitive deficits in AD mice. The expression levels of CaSR were increased both in AD mice and Aβ1–42 (β-amyloid protein)-treated primary cultured neurons. Pharmacological inhibition of CaSR ameliorated recognitive and spatial memory deficits of Aβ1–42-oligomer-treated mice in a dose-dependent manner. Pharmacological inhibition of CaSR or down-regulation of the expression of CaSR by CaSR-shRNA-lentivirus prevented the impairment of filopodia, and the synapse induced by oligomeric Aβ1–42. The contents of cytosolic phospholipase A2 (cPLA2) and prostaglandin E2 (PGE2) in hippocampal neurons and tissue were increased after treatment with Aβ1–42 oligomers. Inhibition or down-regulation of CaSR mediates Aβ-induced synapse formation and cognitive deficits partially, through the activation of the cPLA2/PGE2 pathway. This study provides novel insights on CaSR, which is a promising therapeutic target for AD.

Highlights

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases with a slow and gradual deterioration of the memory that affects language, personality, and cognitive control (Wyss-Coray and Rogers, 2012; Mhatre et al, 2014; Dos Santos Picanco et al, 2018)
The increase expression or activity of calcium-sensing receptor (CaSR) mediates the AD-like phenotypes/pathology induced by Aβ1–42 oligomers partially through activation of the Cytosolic Phospholipase A2 (cPLA2)/Prostaglandin E2 (PGE2) pathway
CaSR is located in nerve terminals which are related to synaptic plasticity and neuronal transmission (Bandyopadhyay et al, 2010)

Summary

Introduction

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases with a slow and gradual deterioration of the memory that affects language, personality, and cognitive control (Wyss-Coray and Rogers, 2012; Mhatre et al, 2014; Dos Santos Picanco et al, 2018). It is well demonstrated that soluble oligomers of Aβ is the pertinent toxic form of Aβ C. et al, 2016; Wang T. et al, 2016) Both others, and our previous studies have shown that soluble Aβ oligomers could decrease the number of dendritic spines and inhibit the long-term potentiation (LTP), leading to the decline of cognitive function in AD mice (Price et al, 2014; Jiang et al, 2016). Disrupting synapse function plays an important role in the memory deficits of AD, which stands out in early AD pathological changes (Price et al, 2014; Teich et al, 2015; Wang X. et al, 2018).

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