Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store

Abstract

Summary Evidence accumulated over more than two decades has implicated Ca 2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to the Ca 2+ hypothesis of brain aging and dementia. Electrophysiological, imaging, and behavioral studies in hippocampal or cortical neurons of rodents and rabbits have revealed aging‐related increases in the slow afterhyperpolarization, Ca 2+ spikes and currents, Ca 2+ transients, and L‐type voltage‐gated Ca 2+ channel (L‐VGCC) activity. Several of these changes have been associated with age‐related deficits in learning or memory. Consequently, one version of the Ca 2+ hypothesis has been that increased L‐VGCC activity drives many of the other Ca 2+ ‐related biomarkers of hippocampal aging. In addition, other studies have reported aging‐ or AD model‐related alterations in Ca 2+ release from ryanodine receptors (RyR) on intracellular stores. The Ca 2+ ‐sensitive RyR channels amplify plasmalemmal Ca 2+ influx by the mechanism of Ca 2+ ‐induced Ca 2+ release (CICR). Considerable evidence indicates that a preferred functional link is present between L‐VGCCs and RyRs which operate in series in heart and some brain cells. Here, we review studies implicating RyRs in altered Ca 2+ regulation in cell toxicity, aging, and AD. A recent study from our laboratory showed that increased CICR plays a necessary role in the emergence of Ca 2+ ‐related biomarkers of aging. Consequently, we propose an expanded L‐VGCC/Ca 2+ hypothesis, in which aging/pathological changes occur in both L‐type Ca 2+ channels and RyRs, and interact to abnormally amplify Ca 2+ transients. In turn, the increased transients result in dysregulation of multiple Ca 2+ ‐dependent processes and, through somewhat different pathways, in accelerated functional decline during aging and AD.

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Cited by papers we hold 2

• Biometal Dyshomeostasis and Toxic Metal Accumulations in the Development of Alzheimer’s Disease · 2017
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• Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain · 2016
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