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Calcineurin inhibition alters APP metabolism in vitro and in vivo
Abstract   Peer reviewed

Calcineurin inhibition alters APP metabolism in vitro and in vivo

Aleister Saunders, Suruchi Utreja, Brie Paddock, Sean Miller and Daniel R. Marenda
Alzheimer's & dementia, v 8(4S Part 6), pp P209-P209
Jul 2012
DOI: https://doi.org/10.1016/j.jalz.2012.05.2139

Abstract

Background APP metabolism plays a central role in Alzheimer's disease (AD) pathogenesis. APP metabolism is complex and includes gene/protein expression, trafficking, post-translational modification, and regulated intramembraneous proteolysis. To identify these genes we carried out human cell-based genetic screen for APP metabolism regulators, by individually knocking-down human genes located in regions of the human genome implicated by genetic studies. Methods Bioinformatic tools were used to identify all genes in regions of Chr. 9 and Chr. 10 genetically linked to AD. Calcineurin (CaN) expression was knocked-down or over-expressed in human cell lines. FK506 was used to inhibit CaN activity in cells and in a transgenic Drosophila AD models. Western blot and ELISA analysis of human cell lines and Drosophila brains was used to assess alteration in APP metabolism. The effect of CaN inhibition on Drosophila complex motor function, learning and memory was also investigated. Results We demonstrate that knock-down and over-expression of CaN catalytic (PPP3CB) and regulatory (PPP3R2) subunits alters APP metabolism in human cell lines. FK506 mediated inhibition of CaN activity resulted in similar effects as catalytic subunit knock-down. Using two Drosophila AD models, we demonstrate that CaN inhibition alters APP processing, reduces Abeta puncta in Drosophila brain, reduces complex motor function deficits, and reduces memory deficits. Conclusions This work demonstrates that CaN regulates APP metabolism in vitro and in vivo. Inhibition of calcineurin with FDA approved drugs results in reduction of AD related phenotypes in vivo. This suggests that targeting CaN may have clinical relevance in the treatment of AD.

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