Abstract
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.
Highlights
Alzheimer Disease (AD) is the most common type of dementia characterized clinically by progressive deterioration of cognitive functions including memory, reasoning, and language [1]
We showed that dantrolene-induced lowering of ryanodine receptor (RyR)-mediated Ca2+ release leads to the reduction of β Amyloid precursor protein (βAPP) cleavage by β- and γ-secretases and decreases both intracellular and extracellular Amyloid β peptide (Aβ) load in wild type βAPP- or βAPPswe- overexpressing neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice brain
It highlights the molecular mechanisms that could influence RyRmediated Ca2+ release in AD where PS and Aβ emerge as detrminant regulators of RyR expression and function alteration
Summary
Alzheimer Disease (AD) is the most common type of dementia characterized clinically by progressive deterioration of cognitive functions including memory, reasoning, and language [1]. We showed that dantrolene-induced lowering of RyR-mediated Ca2+ release leads to the reduction of βAPP cleavage by β- and γ-secretases and decreases both intracellular and extracellular Aβ load in wild type βAPP- or βAPPswe- overexpressing neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice brain. Long-term pharmacological blockade of RYR with dantrolene in APPswe/PSL166P mice resulted in the loss of synaptic markers, and neuronal atrophy in hippocampal and cortical regions [78] Based on these results, one could assume that alteration of RyR-mediated Ca2+ signals along AD pathogenesis progression may shift cell behavior from a protective/adaptive response to a pro-apoptotic phenotype.
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