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

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.