Potential pathogenic role of beta-amyloid(1-42)-aluminum complex in Alzheimer's disease.
The etiopathogenesis of Alzheimer's disease is far from being clearly understood. However, the involvement of metal ions as a potential key factor towards conformational modifications and aggregation of amyloid is widely recognized. The aim of the present study is to shed some light on the relationship between metal ions, amyloid conformation/aggregation, and their potential relationship with the conformational aspects of AD. We compare the effects of beta-amyloid(1-42) and its various metal complexes (beta-amyloid-Al, beta-amyloid-Zn, beta-amyloid-Cu, beta-amyloid-Fe) in human neuroblastoma cells in terms of cell viability, membrane structure properties, and cell morphology. No significant toxic effects were observed in neuroblastoma cells after 24h treatment both with beta-amyloid and beta-amyloid-metals (beta-amyloid-Zn, beta-amyloid-Cu, beta-amyloid-Fe); on the other hand, there was a marked reduction of cellular viability after treatment with beta-amyloid-Al complex. In addition, treatment with beta-amyloid-Al increased membrane fluidity much more than other beta-amyloid-metal complexes, whose contribution was negligible. Furthermore, the cellular morphology, as observed by electron microscopy, was deeply altered by beta-amyloid-Al. Importantly, beta-amyloid-Al toxicity is closely and significantly associated with a great difference in the structure/aggregation of this complex with respect to that of beta-amyloid alone and other beta-amyloid-metal complexes. In addition, beta-amyloid, as a consequence of Al binding, becomes strongly hydrophobic in character. These findings show a significant involvement of Al, compared to the other metal ions used in our experiments, in promoting a specific amyloid(1-42) aggregation, which is able to produce marked toxic effects on neuroblastoma cells, as clearly demonstrated for the first time in this study.
Department of Biology, University of Padova, Viale G. Colombo, 3-35121 Padova, Italy.
Denise
D
Drago
Mikol
M
Bettella
Silvia
S
Bolognin
Laura
L
Cendron
Janez
J
Scancar
Radmila
R
Milacic
Fernanda
F
Ricchelli
Angela
A
Casini
Luigi
L
Messori
Giuseppe
G
Tognon
Paolo
P
Zatta
D000535:Aluminum / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D005454:Fluorescence Polarization; D006801:Humans; D013058:Mass Spectrometry; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission
D000682:Amyloid; D000535:Aluminum