Knockdown of Amyloid Precursor Protein Increases Calcium Levels in the Endoplasmic Reticulum

Overview

Journal Sci Rep

Specialty Science

Date 2017 Nov 8

PMID 29109429

Citations 10

Authors

Kinga Gazda

Jacek Kuznicki

Tomasz Wegierski

Affiliations

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Abstract

Familial Alzheimer's disease (AD) is caused by mutations in the genes that encode amyloid precursor protein (APP) and presenilins. Disturbances in calcium homeostasis have been observed in various cellular and animal models of AD and are proposed to underlie the pathogenesis of the disease. Furthermore, wildtype presenilins were shown to regulate endoplasmic reticulum (ER) calcium homeostasis, although their precise mechanism of action remains controversial. To investigate whether APP also affects ER calcium levels, we used RNA interference to target the APP gene in cultured T84 cells in combination with two types of ER calcium sensors. Using a genetically encoded calcium indicator, GEM-CEPIA1er, we found that APP-deficient cells exhibited elevated resting calcium levels in the ER and prolonged emptying of ER calcium stores upon the cyclopiazonic acid-induced inhibition of sarco-endoplasmic reticulum calcium-ATPase. These effects could be ascribed to lower ER calcium leakage rates. Consistent with these results, translocation of the endogenous ER calcium sensor STIM1 to its target channel Orai1 was delayed following ER calcium store depletion. Our data suggest a physiological function of APP in the regulation of ER calcium levels.

Citing Articles

Knockdown of Amyloid Precursor Protein Increases Ion Channel Expression and Alters Ca Signaling Pathways.

Paschou M, Liaropoulou D, Kalaitzaki V, Efthimiopoulos S, Papazafiri P Int J Mol Sci. 2023; 24(3).

PMID: 36768625 PMC: 9917207. DOI: 10.3390/ijms24032302.

Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases.

Tedeschi V, La Russa D, Franco C, Vinciguerra A, Amantea D, Secondo A Cells. 2021; 10(10).

PMID: 34685498 PMC: 8533710. DOI: 10.3390/cells10102518.

APPsα rescues impaired Ca homeostasis in APP- and APLP2-deficient hippocampal neurons.

Ludewig S, Herrmann U, Michaelsen-Preusse K, Metzdorf K, Just J, Bold C Proc Natl Acad Sci U S A. 2021; 118(26).

PMID: 34172567 PMC: 8256088. DOI: 10.1073/pnas.2011506118.

Alterations of the Endoplasmic Reticulum (ER) Calcium Signaling Molecular Components in Alzheimer's Disease.

Chami M, Checler F Cells. 2020; 9(12).

PMID: 33271984 PMC: 7760721. DOI: 10.3390/cells9122577.

Putative autoantibodies in the cerebrospinal fluid of Alzheimer's disease patients.

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