Ryanodine receptors: physiological function and deregulation in Alzheimer disease

Molecular Neurodegeneration

Mounia Chami²  Frédéric Checler²  Dolores Del Prete¹ 

[1] Present address: Albert Einstein College of Medicine, Bronx, New York 10461NY, USA;CNRS, IPMC, Sophia Antipolis, Nice, F-06560 Valbonne, France

关键词: Amyloid beta;    Amyloid precursor protein;    Presenilin;    Neurodegeneration;    Endoplasmic reticulum;    Alzheimer disease;    Calcium;    Ryanodine receptor;   

Others  :  861447
DOI  :  10.1186/1750-1326-9-21

 received in 2014-01-14, accepted in 2014-05-18,  发布年份 2014

【 摘 要 】

Perturbed Endoplasmic Reticulum (ER) calcium (Ca²⁺) homeostasis emerges as a central player in Alzheimer disease (AD). Accordingly, different studies have reported alterations of the expression and the function of Ryanodine Receptors (RyR) in human AD-affected brains, in cells expressing familial AD-linked mutations on the β amyloid precursor protein (βAPP) and presenilins (the catalytic core in γ-secretase complexes cleaving the βAPP, thereby generating amyloid β (Aβ) peptides), as well as in the brain of various transgenic AD mice models. Data converge to suggest that RyR expression and function alteration are associated to AD pathogenesis through the control of: i) βAPP processing and Aβ peptide production, ii) neuronal death; iii) synaptic function; and iv) memory and learning abilities. In this review, we document the network of evidences suggesting that RyR could play a complex dual “compensatory/protective versus pathogenic” role contributing to the setting of histopathological lesions and synaptic deficits that are associated with the disease stages. We also discuss the possible mechanisms underlying RyR expression and function alterations in AD. Finally, we review recent publications showing that drug-targeting blockade of RyR and genetic manipulation of RyR reduces Aβ production, stabilizes synaptic transmission, and prevents learning and memory deficits in various AD mouse models. Chemically-designed RyR “modulators” could therefore be envisioned as new therapeutic compounds able to delay or block the progression of AD.

【 授权许可】

   
2014 Del Prete et al.; licensee BioMed Central Ltd.

【 图 表 】

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