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Review
. 2010;20 Suppl 2(Suppl 2):S487-98.
doi: 10.3233/JAD-2010-100306.

Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease

Charlene Supnet  1 , Ilya Bezprozvanny
Affiliations
Review

Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease

Charlene Supnet et al. J Alzheimers Dis. 2010.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder among the aged worldwide. AD is characterized by extensive synaptic and neuronal loss that leads to impaired memory and cognitive decline. The cause of AD is not completely understood and no effective therapy has been developed. The accumulation of toxic amyloid-beta42 (Abeta42) peptide oligomers and aggregates in AD brain has been proposed to be primarily responsible for the pathology of the disease, an idea dubbed the 'amyloid hypothesis' of AD etiology. In addition to the increase in Abeta42 levels, disturbances in neuronal calcium (Ca2+) signaling and alterations in expression levels of Ca2+ signaling proteins have been observed in animal models of familial AD and in studies of postmortem brain samples from sporadic AD patients. Based on these data, the 'Ca2+ hypothesis of AD' has been proposed. In particular, familial AD has been linked with enhanced Ca2+ release from the endoplasmic reticulum and elevated cytosolic Ca2+ levels. The augmented cytosolic Ca2+ levels can trigger signaling cascades that affect synaptic stability and function and can be detrimental to neuronal health, such as activation of calcineurin and calpains. Here we review the latest results supporting the 'Ca2+ hypothesis' of AD pathogenesis. We further argue that over time, supranormal cytosolic Ca2+ signaling can impair mitochondrial function in AD neurons. We conclude that inhibitors and stabilizers of neuronal Ca2+ signaling and mitochondrial function may have therapeutic potential for AD treatment. We also discuss latest and planned AD therapeutic trials of agents targeting Ca2+ channels and mitochondria.

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Figures

Figure 1
Figure 1. The compartmentalization of intracellular Ca2+ signalling in neurons and AD pathogenesis
Calcium (Ca2+) is a key regulator of many neuronal processes and serves as the critical link between environmental stimuli and the intracellular effectors that result in a physiological response (Berridge, 1998). Gene expression, protein processing, ATP production, neurotransmitter release, action potential generation, modulation of membrane excitability, short-term and long-term synaptic plasticity, neurite outgrowth and control of cell death mechanisms are Ca2+-regulated processes that are imperative for neuronal function. The proteins that bind free Ca2+, such as calmodulin (CaM), and activate Ca2+-dependent cellular processes are expressed in membrane enclosed compartments such as the cytoplasm, the endoplasmic reticulum (ER) or the mitochondria (mt). The concentration of free Ca2+ ([Ca2+]) and the spatio-temporal pattern of Ca2+ microdomains determines the activation of particular cellular processes (Berridge, 2006). Thus, the [Ca2+] in each compartment is tightly regulated. Plasma membrane Ca2+ ATPases (PMCA), sodium/calcium exchangers (NCX) and sarco-/endoplasmic reticulum Ca2+ ATPases (SERCA) set up an electrochemical gradient which, upon neuronal activation, Ca2+ ions can passively move between cellular compartments through voltage- and/or ligand-gated channels. Calcium influx from the extracellular matrix can happen through voltage-gated Ca2+ channels (VGCC), N-methyl-D-aspartate receptors (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), store-operated channels (SOC, eg. transent receptor potential channels (TRPC)). Calcium efflux from intracellular ER stores is mediated by inositol 1,4,5-trisphosphate receptors (IP3R), ryanodine receptors (RyanR) and presenilins (PSEN) which facilitate “ER Ca2+ leak” (Tu et al., 2006). Mitochondria participate in Ca2+ signaling by taking up Ca2+ from cytosolic or ER microdomains across the outer mitochondrial membrane (OMM) through unknown mechanisms, likely through the voltage-dependent anion channel (VDAC) into the inner mitochondrial membrane (IMM) lumen through the mitochondrial Ca2+ uniporter (MCU). Recently, a Ca2+/H+ anti-porter (leucine zipper EF-hand–containing transmembrane protein 1, Letm1) that transports Ca2+ from the cytosol into the IMM lumen in was identified in HeLa cells (Jiang et al., 2009) but its function in neurons is unknown. Polymorphisms in TOMM40 gene encoding outer mitochondrial membrane component of the TOM complex have been linked with the probability of developing late-onset AD (Potkin et al., 2009; Roses et al., 2009; Shen et al., 2010; Takei et al., 2009). Calcium equilibrium is maintained along the IMM by NCX or hydrogen/calcium exchangers (HCX). Opening of the mitochondrial permeability transition pore (mtPTP) allows large efflux of Ca2+ from the IMM lumen and is often a trigger for the cell death signalling cascade (Giacomello et al., 2007). Under normal circumstances following neuronal stimulation, active Ca2+ transport returns [Ca2+] in each compartment to homeostatic levels. Both active and passive Ca2+ handling mechanisms are subject to regulation, in fact, Ca2+ itself is an important regulator of Ca2+ channel activity.
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