Ryanodine receptors: physiological function and deregulation in Alzheimer disease

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.

Figure 1

Amyloidogenic and non-amyloidogenic pathways of β amyloid precursor protein (βAPP) processing. Aβ peptides are derived from the processing of the βAPP through the amyloidogenic pathway, implicating β-secretase (BACE1) and γ-secretase complex (composed of PS1 or PS2, Nicastrin, anterior pharynx-defective-1 (APH-1), and presenilin enhancer-2 (PEN-2)). Aβ production is abolished when βAPP is processed through the non-amyloidogenic pathway implicating α-secretase and γ-secretase complexes.

Figure 2

Neuronal Ca²⁺ signaling. Cytosolic [Ca²⁺]_i rises are the result of an influx across the plasma membrane via voltage-gated Ca²⁺channels (VGCCs), ionotropic glutamate receptors (N-Methyl-D-Aspartic acid receptors, NMDARs; and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate, AMPARs), and the release from the ER through the inositol 1,4,5-trisphosphate (IP₃R) and the ryanodine (RyR) receptors. Intraneuronal Ca²⁺ compartmentalization, is also maintained by the activity of Ca²⁺-binding buffering proteins (e.g., calbindin and parvalbumin), and regulated within signaling microdomains which involve, ATP-dependent Ca²⁺ pumps SERCA (Sarco-Endoplasmic Reticulum Ca²⁺ ATPase) accumulating Ca²⁺ from the cytosol to ER, and the sodium-Ca²⁺ exchanger (Na⁺/Ca²⁺), which act together with PMCA (Plasma Membrane Ca²⁺ ATPase) to restore [Ca²⁺]_i back to resting levels by extruding Ca²⁺ from the cytosol to the extracellular space. Although much of the Ca²⁺ entry into neuron is predominantly mediated by plasma membrane channels, IP₃R- and/or RyR-mediated Ca²⁺ release can be subsequently recruited via the phenomenon of Ca²⁺-induced Ca²⁺ release (CICR), a regenerative process in which Ca²⁺ enhances its own release from IP₃R and RyR.

Figure 3

Scheme of the implication of RyR expression and function alterations in AD. RyR-mediated AD pathogenesis occurs through Ca²⁺ signaling dysregulation, the amplification of βAPP metabolism and Aβ peptide production, the control of neuronal death and degeneration, synaptic dysfunction, and learning and memory decline. The functional cross talk between these AD “pathological hallmarks” places RyR at the crossroads of AD pathogenesis.