含α4的烟碱型乙酰胆碱受体缺失对Tg2576小鼠Aβ相关神经病理学具有保护作用的证据。

Evidence for a protective effect of the loss of α4-containing nicotinic acetylcholine receptors on Aβ-related neuropathology in Tg2576 mice.

作者信息

Vilella Antonietta, Romoli Benedetto, Bodria Martina, Pons Stéphanie, Maskos Uwe, Zoli Michele

机构信息

Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.

Institut Pasteur, Université Paris Cité, Neurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, Département de Neuroscience, Paris, France.

出版信息

Front Neurosci. 2023 Apr 11;17:1097857. doi: 10.3389/fnins.2023.1097857. eCollection 2023.

DOI:10.3389/fnins.2023.1097857

PMID:37113156

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10126303/

Abstract

INTRODUCTION

Loss of cholinergic neurons as well as α4β2* (* = containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer's disease (AD). Specifically, amyloid β (Aβ), the principal pathogenic factor of AD, is a high affinity ligand for nAChRs. Yet, the pathophysiological role of nAChRs in AD is not well established.

METHODS

In the present study, we have investigated the effects of the loss of α4* nAChRs on the histological alterations of the Tg2576 mouse model of AD (APPswe) crossing hemizygous APPswe mice with mice carrying the genetic inactivation of α4 nAChR subunit (α4KO).

RESULTS

A global decrease in Aβ plaque load was observed in the forebrain of APPswe/α4KO mice in comparison with APPswe mice, that was particularly marked in neocortex of 15 month-old mice. At the same age, several alterations in synaptophysin immunoreactivity were observed in cortico-hippocampal regions of APPswe mice that were partially counteracted by α4KO. The analysis of the immunoreactivity of specific astroglia (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule, Iba1) markers showed an increase in the number as well as in the area occupied by these cells in APPswe mice that were partially counteracted by α4KO.

CONCLUSION

Overall, the present histological study points to a detrimental role of α4* nAChRs that may be specific for Aβ-related neuropathology.

摘要

引言

胆碱能神经元以及α4β2*（* = 含）烟碱型乙酰胆碱受体（nAChRs）的丧失是阿尔茨海默病（AD）的一个显著特征。具体而言，AD的主要致病因素淀粉样β蛋白（Aβ）是nAChRs的高亲和性配体。然而，nAChRs在AD中的病理生理作用尚未明确。

方法

在本研究中，我们通过将半合子APPswe小鼠与携带α4 nAChR亚基基因失活（α4KO）的小鼠杂交，研究了α4* nAChRs丧失对AD的Tg2576小鼠模型（APPswe）组织学改变的影响。

结果

与APPswe小鼠相比，在APPswe/α4KO小鼠的前脑中观察到Aβ斑块负荷整体下降，这在15月龄小鼠的新皮层中尤为明显。在相同年龄，在APPswe小鼠的皮质 - 海马区域观察到突触素免疫反应性的几种改变，而α4KO可部分抵消这些改变。对特定星形胶质细胞（胶质纤维酸性蛋白，GFAP）和小胶质细胞（离子钙结合衔接分子，Iba1）标志物免疫反应性的分析表明，在APPswe小鼠中这些细胞的数量以及所占面积增加，而α4KO可部分抵消这一现象。