FAD mutations in amyloid precursor protein do not directly perturb intracellular calcium homeostasis.

Emily Stieren,Amina El Ayadi,Fuzhen Li,Darren Boehning,Walter P Werchan

doi:10.1371/journal.pone.0011992

Emily Stieren, Amina El Ayadi + Show 3 more

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https://doi.org/10.1371/journal.pone.0011992

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Journal: PloS one	Publication Date: Aug 5, 2010
Citations: 26	License type: CC BY 4.0

Affiliation: The University of Texas Medical Branch at Galveston

Abstract

Disturbances in intracellular calcium homeostasis are likely prominent and causative factors leading to neuronal cell death in Alzheimer's disease (AD). Familial AD (FAD) is early-onset and exhibits autosomal dominant inheritance. FAD-linked mutations have been found in the genes encoding the presenilins and amyloid precursor protein (APP). Several studies have shown that mutated presenilin proteins can directly affect calcium release from intracellular stores independently of Aβ production. Although less well established, there is also evidence that APP may directly modulate intracellular calcium homeostasis. Here, we directly examined whether overexpression of FAD-linked APP mutants alters intracellular calcium dynamics. In contrast to previous studies, we found that overexpression of mutant APP has no effects on basal cytosolic calcium, ER calcium store size or agonist-induced calcium release and subsequent entry. Thus, we conclude that mutated APP associated with FAD has no direct effect on intracellular calcium homeostasis independently of Aβ production.

Highlights

Alzheimer’s disease (AD) is a progressive neurological disorder characterized by deterioration of cognitive abilities
We focused on six different well-characterized Familial AD (FAD)-linked amyloid precursor protein (APP) mutants that affect b-secretase cleavage, fibrillization, and c-secretase cleavage (Figure 1A)
As APP is trafficked through the secretory pathway, a series of glycosylation events occur leading to a mature, or fully glycosylated, protein with slower mobility on SDS-PAGE

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurological disorder characterized by deterioration of cognitive abilities. According to the predominant amyloid cascade hypothesis, AD pathogenesis is associated with a series of molecular events which leads to the extracellular deposition and aggregation of specific proteolytic fragments of APP. These aggregated protein fragments constitute the core of extracellular senile amyloid plaques, a pathologic hallmark of AD. APP is cleaved by a series of enzymes, called secretases, generating proteolytic fragments of various lengths. The principal cleavage event is by a-secretase, which generates a large soluble ectodomain (APPs) that is secreted into the extracellular space and a C-terminal fragment (C83) that remains in the membrane [3]. The Ab42 peptide is more prone to aggregation and is considered to be more cytotoxic than the shorter Ab species [4]

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