Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons

Bei Wu, Hiroo Yamaguchi, F. Anthony Lai, Jie Shen

    Research output: Contribution to journalArticle

    48 Citations (Scopus)

    Abstract

    Presenilin (PS) plays a central role in the pathogenesis of Alzheimer's disease, and loss of PS causes progressive memory impairment and age-related neurodegeneration in the mouse cerebral cortex. In hippocampal neurons, PS is essential for neurotransmitter release, NMDA receptor-mediated responses, and long-term potentiation. PS is also involved in the regulation of calcium homeostasis, although the precise site of its action is less clear. Here we investigate the mechanism by which PS regulates synaptic function and calcium homeostasis using acute hippocampal slices from PS conditional knockout mice and primary cultured postnatal hippocampal neurons, in which PS is inducibly inactivated. Using two different calcium probes, Fura-2 and Mag -Fura-2, we found that inactivation of PS in primary hippocampal neurons does not affect calcium concentration in the endoplasmic reticulum. Rather, in the absence of PS, levels of ryanodine receptor (RyR) are reduced in the hippocampus, measured by Western analysis and radioligand binding assay, although the mRNA expression is unaffected. RyR-mediated function is also impaired, as indicated by reduced RyR agonist-induced calcium release from the ER and RyR-mediated synaptic responses in the absence of PS. Furthermore, knockdown of RyR expression in wild-type hippocampal neurons by two independent shRNAs to levels comparable with the RyR protein reduction in PS-deficient hippocampal neurons mimics the defects exhibited in calcium homeostasis and presynaptic function. Collectively, our findings show that PS regulates calcium homeostasis and synaptic function via RyR and suggest that disruption of intracellular calcium homeostasis may be an early pathogenic event leading to presynaptic dysfunction in Alzheimer's disease.

    Original languageEnglish
    Pages (from-to)15091-15096
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number37
    DOIs
    Publication statusPublished - Sep 10 2013

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    Presenilins
    Ryanodine Receptor Calcium Release Channel
    Homeostasis
    Calcium
    Neurons
    Alzheimer Disease
    Radioligand Assay
    Long-Term Potentiation
    Fura-2
    N-Methyl-D-Aspartate Receptors
    Knockout Mice
    Endoplasmic Reticulum
    Cerebral Cortex
    Neurotransmitter Agents

    All Science Journal Classification (ASJC) codes

    • General

    Cite this

    Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. / Wu, Bei; Yamaguchi, Hiroo; Lai, F. Anthony; Shen, Jie.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 37, 10.09.2013, p. 15091-15096.

    Research output: Contribution to journalArticle

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