Potential Astrocytic Receptors and Transporters in the Pathogenesis of Alzheimer’s Disease

Article type: Review Article

Authors: Zhang, Xiaohua^{a; 1} | Lao, Kejing^{a; 1} | Qiu, Zhongying^a | Rahman, Md Saidur^{a; b} | Zhang, Yuelin^{a; *} | Gou, Xingchun^{a; *}

Affiliations: [a] Shaanxi Key Laboratory of Brain Disorders & Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, P.R. China | [b] Institute of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, P.R. China

Correspondence: [*] Correspondence to: Xingchun Gou and Yuelin Zhang, Shaanxi Key Laboratory of Brain Disorders & Institute of Basic and Translational Medicine, Xi’an Medical University, No. 1 Xinwang Road, Xi’an 710021, China. Tel.: +86 29 86177603; Fax: +86 29 86177603; E-mails: gouxingchun@189.cn (X. Gou) and Zhangyuelin68@163.com (Y. Zhang).

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by the progressive loss of memory and cognition in the aging population. However, the etiology of and therapies for AD remain far from understood. Astrocytes, the most abundant neuroglia in the brain, have recently aroused substantial concern due to their involvement in synaptotoxicity, amyloidosis, neuroinflammation, and oxidative stress. In this review, we summarize the candidate molecules of astrocytes, especially receptors and transporters, that may be involved in AD pathogenesis. These molecules include excitatory amino acid transporters (EAATs), metabotropic glutamate receptor 5 (mGluR5), the adenosine 2A receptor (A2AR), the α7-nicotinic acetylcholine receptor (α7-nAChR), the calcium-sensing receptor (CaSR), S100β, and cannabinoid receptors. We describe the characteristics of these molecules and the neurological and pharmacological underpinnings of these molecules in AD. Among these molecules, EAATs, A2AR, and mGluR5 are strongly related to glutamate-mediated synaptotoxicity and are involved in glutamate transmission or the clearance of extrasynaptic glutamate in the AD brain. The α7-nAChR, CaSR, and mGluR5 are receptors of Aβ and can induce a plethora of toxic effects, such as the production of excess Aβ, synaptotoxicity, and NO production triggered by changes in intracellular calcium signaling. Antagonists or positive allosteric modulators of these receptors can repair cognitive ability and modify neurobiological changes. Moreover, blocking S100β or activating cannabinoid receptors reduces neuroinflammation, oxidative stress, and reactive astrogliosis. Thus, targeting these molecules might provide alternative approaches for treating AD.

Keywords: A2AR, α7-nAChR, Alzheimer’s disease, astrocytes, cannabinoid receptor 2, CaSR, EAATs, mGluR5, S100β

DOI: 10.3233/JAD-181084

Journal: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1109-1122, 2019