. SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol. 2008 Jun 30;181(7):1107-16. PubMed.


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  1. 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.


    . Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 2008 Jun 26;58(6):871-83. PubMed.

    . A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell. 2008 Jun 27;133(7):1149-61. PubMed.

    . Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J Neurosci. 2006 Mar 29;26(13):3482-90. PubMed.

    . Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol. 2000 May 15;149(4):793-8. PubMed.

    . 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. 2004 Jan 14;24(2):508-13. PubMed.

    . Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell. 2006 Sep 8;126(5):981-93. PubMed.

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