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.

Fig. 1

Ryanodine protection of older cultured hippocampal neurons from excitotoxicity. Following a glutamate insult, older cultured neurons exhibit a sustained [Ca²⁺]_i elevation leading to cell death. Confocal indo-1 Ca²⁺ imaging shows ryanodine facilitated the recovery (decline) of the Ca²⁺ plateau and protected older neurons following glutamate insult (modified from Clodfelter et al. copyright 2002 with permission from Elsevier).

Fig. 2

Ryanodine reduces the slow afterhyperpolarization (AHP) in an age-dependent manner. (A) Representative example of the blocking effect of 20 µm ryanodine on the AHP of a 23-month-old rat CA1 neuron. (B) Age dependence of slow AHP (sAHP) amplitude, before and following ryanodine application. (C) Age dependence of slow AHP duration, pre- and postryanodine. (D) Age dependence of medium AHP (mAHP) amplitude, pre- and postryanodine. (E) Age-dependence measures of spike-frequency accommodation, pre- and postryanodine. * indicates a significant difference from the 4-month-old group (P < 0.05). Note that aging changes in sAHP markers emerge at 12 months of age (preryanodine group), and ryanodine completely eliminates the aging effects (B and C), indicating a selective blockade of the aging-related increase in Ca²⁺-induced Ca²⁺ release (CICR). The initial mAHP is not modulated by CICR (A) and its age dependence was not altered by ryanodine (D). Action potential accommodation changes generally followed the sAHP pattern, but the aging effect at 12 months was not significant in this subset of cells (mean ± SEM) (from Gant et al. copyright 2006 with permission from the Society for Neuroscience).

Fig. 3

Ryanodine-sensitive component of the [Ca²⁺]_i rise during repetitive synaptic stimulation. Ca²⁺-induced Ca²⁺ release (CICR) contribution to the [Ca²⁺]_i rise was determined by subtracting [Ca²⁺]_i measures following ryanodine from those before ryanodine application (Δ[Ca²⁺]_i), in neurons from 4- and 23-month-old animals during 20-s trains of 7 Hz suprathreshold synaptic stimulation. Values shown represent only the (CICR) component of the Ca²⁺ response that was blocked by ryanodine. Note that the ryanodine-sensitive component of [Ca²⁺]_i is significantly greater in aged rat neurons and contributes to the Ca²⁺ response primarily during the first 5 s of stimulation. * indicates a significant difference from the 4-month-old group (P < 0.05). (mean ± SEM).

Fig. 4

Schematic model of alterations in L-type voltage-gated Ca²⁺ channels (L-VGCC) and Ca²⁺-induced Ca²⁺ release (CICR) that drive other Ca²⁺-related hippocampal biomarkers of aging. With aging, increased L-VGCC activity and enhanced CICR operate in series, amplifying the impact of Ca²⁺ influx on multiple Ca²⁺-dependent functions. The thickness of arrows schematically represents the activity of Ca²⁺ flux or signaling pathways in aged rat neurons (B) relative to young (A). These pathways are increased at several stages despite equivalent spike amplitudes and durations. Dashed arrows indicate a possible direct parallel contribution of L-VGCCs to [Ca²⁺]_i (From Gant et al. copyright 2006 with permission from the Society for Neuroscience).