title: Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store.
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.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky, University of Kentucky Medical Center, Lexington, KY 40536, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Thibault
authors.forename: John C
authors.initials: JC
authors.lastname: Gant
authors.forename: Philip W
authors.initials: PW
authors.lastname: Landfield
mesh_terms: D000368:Aged; D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000737:chemistry; D001921:Brain / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D004594:Electrophysiology; D006801:Humans; D007511:Ischemia; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D015415:Biomarkers; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium