This article by Gabrielle Strobel provides an excellent review of recent research advances analyzing the nature and timing of calcium dysregulation in brain neurons of Alzheimer disease (AD) model mice, particularly highlighting the elegant imaging and electrophysiological studies of ryanodine receptor (RyRs) function by Grace Stutzmann and her colleagues. This work is clearly exciting and promising. However, it also seems important to view it in the context of dynamic age-dependent changes and potential interactions with other pathways in Ca2+ dysregulation. The effect of presenilin mutations on Ca2+ release from RyRs is likely to reflect only one stage of a complex cascade of abnormal Ca2+ signaling that, as the article noted, may begin well before hallmark pathology appears, perhaps during normal aging.

For example, early in the development of the Ca2+ hypothesis, we found evidence of increased Ca2+ signaling and voltage-gated Ca2+ influx in hippocampal neurons during normal aging in rats (Landfield and Pitler, 1984). This observation has been extended since by imaging...  Read more

This article by Gabrielle Strobel provides an excellent review of recent research advances analyzing the nature and timing of calcium dysregulation in brain neurons of Alzheimer disease (AD) model mice, particularly highlighting the elegant imaging and electrophysiological studies of ryanodine receptor (RyRs) function by Grace Stutzmann and her colleagues. This work is clearly exciting and promising. However, it also seems important to view it in the context of dynamic age-dependent changes and potential interactions with other pathways in Ca2+ dysregulation. The effect of presenilin mutations on Ca2+ release from RyRs is likely to reflect only one stage of a complex cascade of abnormal Ca2+ signaling that, as the article noted, may begin well before hallmark pathology appears, perhaps during normal aging.

For example, early in the development of the Ca2+ hypothesis, we found evidence of increased Ca2+ signaling and voltage-gated Ca2+ influx in hippocampal neurons during normal aging in rats (Landfield and Pitler, 1984). This observation has been extended since by imaging and single channel recording studies (Thibault et al., 1996; Thibault et al., 2001; Hemond and Jaffe, 2005), and such increased Ca2+-dependent processes have been shown to be relevant to age-associated learning deficits (Disterhoft et al., 2004). Furthermore, a recent age course study found that onset of increased Ca2+ release from RyRs with normal aging may underlie wide disturbances in Ca2+-dependent processes (Gant et al., 2006), conceivably, in tandem with or in response to increased influx through voltage-gated Ca2+ channels (Thibault et al., 2007).

As Stutzmann has pointed out, presenilin mutations alone, although they account for the effect on RyR Ca2+ release, are not sufficient to induce pathological hallmarks of AD or neurodegeneration. Moreover, gene mutations account for only a few percent of AD cases. For the vast majority of sporadic cases, then, AD is overwhelmingly a disease of aging. Thus, if Ca2+ dyshomeostasis is indeed a key player in the transition from normal brain aging to AD, our understanding of the role of “calcinopathies” in AD will clearly be informed by unraveling the nature of multiple Ca2+ disturbances at the intersection between normal brain aging and AD.

References:
Landfield PW, Pitler TA (1984) Prolonged Ca2+-dependent after hyperpolarizations in hippocampal neurons of aged rats. Science 226:1089-1092. Abstract

Thibault O, Landfield PW (1996) Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272:1017-1020. Abstract

Thibault O, Hadley R, Landfield PW (2001) Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci 21:9744-9756. Abstract

Hemond P, Jaffe DB (2005) Caloric restriction prevents aging-associated changes in spike-mediated Ca2+ accumulation and the slow afterhyperpolarization in hippocampal CA1 pyramidal neurons. Neuroscience 135:413-420. Abstract

Disterhoft JF, Wu WW, Ohno M (2004) Biophysical alterations of hippocampal pyramidal neurons in learning, ageing and Alzheimer's disease. Ageing Res Rev 3:383-406. Abstract

Gant JC, Sama MM, Landfield PW, Thibault O (2006) Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J Neurosci 26:3482-3490. Abstract

Thibault O, Gant JC, Landfield PW (2007) Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store. Aging Cell 6:307-317. Abstract

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