FAD mutations in amyloid precursor protein do not directly perturb intracellular calcium homeostasis.
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.
Stieren
Emily
E
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Werchan
Walter P
WP
El Ayadi
Amina
A
Li
Fuzhen
F
Boehning
Darren
D
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D050505:Mutant Proteins / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016716:PC12 Cells; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050505:Mutant Proteins; D002118:Calcium