Possible Role of STIM1 Sensor Signal in Memory Loss Connected with Familial Alzheimer's Disease

Abstract

Familial Alzheimer's disease (FAD) which leads to memory impairments is caused by mutations in presenilin-1 (PS1) gene in approximately 40% of cases. PS1 is well known as a component of the gamma-secretase enzyme which cleaves APP to A-beta. To become a catalytic part of enzyme PS1 undergoes an endoproteolysis. It was shown that mutations in PS1 gene disrupt endoproteolysis increasing uncleaved protein level in brain tissue of FAD patients. In our study we found effects of FAD PS1 mutants (PS1DE9, PS1 D247A) on activity of store-operated calcium (SOC) channels in mice hippocampal neurons and Neuro2a cell line. Increased uncleaved PS1 levels led to SOC channels hyperactivities detected with direct single-cell electrophysiological measurements and calcium imaging experiments with fura2-AM. The effects were caused by impaired signal transduction from ER to SOC channels in plasmatic membrane. The impaired intracellular signal transduction by STIM1 sensor was revealed in live confocal imaging experiments and proved with STIM1 knock-down. Moreover, a feeding of Drosophila melanogaster transgenes expressing human mutated PS1 in cholinergic nervous system with pharmacological inhibitor of STIM sensor signal transduction 2APB led to rescue of the memory loss detected by courtship based assay with aged animals. Therefore hyperactive STIM1 signal transduction leads to increased SOC channels activity which could be the reason for memory loss in FAD.This work was supported by the program of “Molecular and Cellular Biology” RAS, research grants from the Russian Basic Research Foundation, Russian Scientific Fund and the President of Russia Scholarship.