Abstract
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 Ca+ 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.
Document Type
Article
Publication Date
4-26-2007
Digital Object Identifier (DOI)
http://dx.doi.org/10.1111/j.1474-9726.2007.00295.x
Repository Citation
Thibault, Olivier; Gant, John C.; and Landfield, Philip W., "Expansion of the Calcium Hypothesis of Brain Aging and Alzheimer's Disease: Minding the Store" (2007). Pharmacology and Nutritional Sciences Faculty Publications. 18.
https://uknowledge.uky.edu/pharmacol_facpub/18
Included in
Medical Nutrition Commons, Medical Pharmacology Commons, Pharmacology, Toxicology and Environmental Health Commons
Notes/Citation Information
Published in Aging Cell, v. 6, issue. 3, 307-317.
2007 Thibault et al. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons AttributionLicense, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.