Recent interesting and new findings by the LaFerla group (Green et al., 2008) add to the growing evidence that AD-related mutations may affect Ca2+ homeostasis, particularly through regulatory pathways controlling intracellular uptake and release mechanisms (e.g., Ca2+-induced Ca2+ release [CICR] via RyRs, ER leak, IP3Rs, SERCA). One note of caution emerging from these studies, however, is the wide diversity of specific cellular mechanisms reported to be sensitive to presenilins and AD-related mutations (Leissring et al., 2000; Stutzmann et al., 2004; Tu et al., 2006; Cheung et al., 2008; Dreses-Werringloer et al., 2008). This diversity raises the question of whether all of these actions reflect physiologically relevant effects on Ca2+ regulation or whether instead the differences might reflect interactions with the varied cell types and experimental conditions employed. In addition, the relationship of these AD mutation effects to alterations in Ca2+ regulation (e.g., increased CICR, L-type voltage-gated Ca2+ channels, afterhyperpolarization, etc.) that occur in normal...  Read more

Recent interesting and new findings by the LaFerla group (Green et al., 2008) add to the growing evidence that AD-related mutations may affect Ca2+ homeostasis, particularly through regulatory pathways controlling intracellular uptake and release mechanisms (e.g., Ca2+-induced Ca2+ release [CICR] via RyRs, ER leak, IP3Rs, SERCA). One note of caution emerging from these studies, however, is the wide diversity of specific cellular mechanisms reported to be sensitive to presenilins and AD-related mutations (Leissring et al., 2000; Stutzmann et al., 2004; Tu et al., 2006; Cheung et al., 2008; Dreses-Werringloer et al., 2008). This diversity raises the question of whether all of these actions reflect physiologically relevant effects on Ca2+ regulation or whether instead the differences might reflect interactions with the varied cell types and experimental conditions employed. In addition, the relationship of these AD mutation effects to alterations in Ca2+ regulation (e.g., increased CICR, L-type voltage-gated Ca2+ channels, afterhyperpolarization, etc.) that occur in normal hippocampal aging (e.g., Gant et al., 2006) or to a new channel that may be important in idiopathic AD (Dreses-Werringloer et al., 2008) remains unclear. These distinctions in fact raise the additional intriguing question of whether there are two types of Ca2+ dysregulation in AD, one that is related to familial AD and one that is related to aging-sensitive, late-onset idiopathic AD. Much further research will be needed to resolve these interesting questions and determine the nature of the intersections between Ca2+ regulation in aging and the different types of AD.

References:
Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK (2008) Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP(3) receptor channel gating. Neuron 58:871-883. Abstract

Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P (2008) A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell 133:1149-1161. 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

Leissring MA, Akbari Y, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM (2000) Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 149:793-798. Abstract

Stutzmann GE, Caccamo A, LaFerla FM, Parker I (2004) Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer's-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 24:508-513. Abstract

Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126:981-993. Abstract

View all comments by Philip Landfield
View all comments by Olivier Thibault

I certainly like the idea that this season might go down in the Alzheimer research history as the summer of calcium, with four major studies recently forging new links between calcium problems in neurons and Alzheimer disease (AD). However, a major issue is how AD-related, deranged calcium signals lead to neuron dysfunction and death.

We have shown a few days ago (Sanz-Blasco et al., 2008) that Aβ oligomers (but not fibrils) promote Ca2+ influx into primary neurons (but not glia). This influx is followed by mitochondrial calcium overload as monitored by photon counting imaging of low-affinity aequorin targeted to mitochondria. The relevance of this finding is that prevention of mitochondrial calcium overload using low concentrations of mitochondrial uncoupler protects neurons against Aβ-induced ROS production, permeability transition, cytochrome c release, and apoptosis and cell death.

Moreover, we found that a series of carboxylic, non-steroidal anti-inflammatory drugs including R-flurbiprofen prevent the mitochondrial calcium overload, acting as mitochondrial...  Read more

I certainly like the idea that this season might go down in the Alzheimer research history as the summer of calcium, with four major studies recently forging new links between calcium problems in neurons and Alzheimer disease (AD). However, a major issue is how AD-related, deranged calcium signals lead to neuron dysfunction and death.

We have shown a few days ago (Sanz-Blasco et al., 2008) that Aβ oligomers (but not fibrils) promote Ca2+ influx into primary neurons (but not glia). This influx is followed by mitochondrial calcium overload as monitored by photon counting imaging of low-affinity aequorin targeted to mitochondria. The relevance of this finding is that prevention of mitochondrial calcium overload using low concentrations of mitochondrial uncoupler protects neurons against Aβ-induced ROS production, permeability transition, cytochrome c release, and apoptosis and cell death.

Moreover, we found that a series of carboxylic, non-steroidal anti-inflammatory drugs including R-flurbiprofen prevent the mitochondrial calcium overload, acting as mitochondrial uncouplers and protecting against cell death. These effects are achieved at NSAID concentrations in the low microM range, well below the range required for targeting γ-secretase. Therefore, mitochondrial calcium overload contributes to cell death induced by Aβ oligomers.

In addition, the long-debated mechanism of neuroprotection by NSAIDs could be related to the calcium hypothesis of Alzheimer disease rather than to their ability to target inflammation or secretases. Whether mitochondrial calcium overload is also involved in cell death induced by excess calcium release promoted by either loss of ER calcium leak or IP3 receptor modulation remains to be established.

References:
Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L. Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS ONE. 2008 Jul 23;3(7):e2718. Abstract

View all comments by Carlos Villalobos