Journal Article

FAD Mutations in Amyloid Precursor Protein Do Not Directly Perturb Intracellular Calcium Homeostasis

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

2010

Overview

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 Abeta 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 Abeta production.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Advertising executives / Age / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-protein / Amyloid beta-Protein Precursor - agonists / Amyloid beta-Protein Precursor - biosynthesis / Amyloid beta-Protein Precursor - genetics / Amyloid beta-Protein Precursor - metabolism / Amyloid precursor protein / Animals / Apoptosis / Autosomal dominant inheritance / Biological Transport - drug effects / Biology / Calcium / Calcium (intracellular) / Calcium - metabolism / Calcium homeostasis / Calcium signalling / Cell death / Cytochrome / Cytosol - metabolism / Endoplasmic reticulum / Endoplasmic Reticulum - drug effects / Endoplasmic Reticulum - metabolism / Gene Expression Regulation / Genetic aspects / Heredity / Homeostasis / Homeostasis - drug effects / Homeostasis - genetics / Humans / Inositol 1,4,5-Trisphosphate Receptors - metabolism / Intracellular / Intracellular Space - drug effects / Intracellular Space - metabolism / Mutant Proteins - agonists / Mutant Proteins - biosynthesis / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutants / Mutation / Neurodegenerative diseases / Neurological Disorders/Alzheimer Disease / Neurological Disorders/Cognitive Neurology and Dementia / Neurological Disorders/Neurogenetics / Neurological Disorders/Neuropsychiatric Disorders / Neuroscience / Neuroscience/Neural Homeostasis / Neuroscience/Neurobiology of Disease and Regeneration / Neuroscience/Neuronal Signaling Mechanisms / Neurosciences / Pathogenesis / PC12 Cells / Peptides / Precursors / Presenilin / Proteins / Rats