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

Evidence accumulated over more than two decades has implicated Ca2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to the Ca2+ 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, Ca2+ spikes and currents, Ca2+ transients, and L‐type voltage‐gated Ca2+ channel (L‐VGCC) activity. Several of these changes have been associated with age‐related deficits in learning or memory. Consequently, one version of the Ca2+ hypothesis has been that increased L‐VGCC activity drives many of the other Ca2+‐related biomarkers of hippocampal aging. In addition, other studies have reported aging‐ or AD model‐related alterations in Ca2+ release from ryanodine receptors (RyR) on intracellular stores. The Ca2+‐sensitive RyR channels amplify plasmalemmal Ca2+ influx by the mechanism of Ca2+‐induced Ca2+ 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 Ca2+ 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 Ca2+‐related biomarkers of aging. Consequently, we propose an expanded L‐VGCC/Ca2+ hypothesis, in which aging/pathological changes occur in both L‐type Ca2+ channels and RyRs, and interact to abnormally amplify Ca2+ transients. In turn, the increased transients result in dysregulation of multiple Ca2+‐dependent processes and, through somewhat different pathways, in accelerated functional decline during aging and AD.