Aluminum modulates effects of beta amyloid(1-42) on neuronal calcium homeostasis and mitochondria functioning and is altered in a triple transgenic mouse model of Alzheimer's disease.
Recent findings suggest that beta-amyloid (A beta) is more neurotoxic when present in its oligomeric configuration rather than as monomers or fibrils. Previous work from our laboratories has shown that A beta aggregation is strongly influenced by the conjugation of the peptide with metal ions (aluminum A, copper [Cu], zinc [Zn], and iron [Fe]) that are found in high concentrations in the core of senile plaques. Disruption of Ca++ signaling and mitochondrial dysfunction are potent triggers of neuronal death and have been implicated in the neuronal loss that is associated with Alzheimer's disease (AD). In this study, we explored whether A beta-metal complexes can have detrimental effects on intraneuronal Ca++ ([Ca++]i) homeostasis and mitochondrial function in vitro. Results from our experiments indicate that, when conjugated with Al, A beta perturbs neuronal [Ca++]i homeostasis and inhibits mitochondrial respiration. Finally, we analyzed the content of the four metals in the brain of a triple transgenic animal model of AD and found that Al is the only one to be increased in the cortex of these mice.
Drago
Denise
D
CNR-Institute for Biomedical Technologies, Padua "Metalloproteins" Unit, Department of Biology, University of Padua, Padua, Italy.
Cavaliere
Alessandra
A
Mascetra
Nicola
N
Ciavardelli
Domenico
D
di Ilio
Carmine
C
Zatta
Paolo
P
Sensi
Stefano L
SL
D000535:Aluminum / Q000378:metabolism / Q000633:toxicity*; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D004195:Disease Models, Animal; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects; D046912:Multiprotein Complexes; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016202:N-Methylaspartate; D000535:Aluminum