Zinc-induced Alzheimer's Abeta1-40 aggregation is mediated by conformational factors.
The heterogeneous precipitates of Abeta that accumulate in the brain cortex in Alzheimer's disease possess varying degrees of resistance to resolubilization. We previously found that Abeta1-40 is rapidly precipitated in vitro by physiological concentrations of zinc, a neurochemical that is highly abundant in brain compartments where Abeta is most likely to precipitate. We now present evidence that the zinc-induced precipitation of Abeta is mediated by a peptide dimer and favored by conditions that promote alpha-helical and diminish beta-sheet conformations. The manner in which the synthetic peptide is solubilized was critical to its behavior in vitro. Zinc-induced Abeta aggregation was dependent upon the presence of NaCl, was enhanced by alpha-helical-promoting solvents, but was abolished when the peptide stock solution was stored frozen. The Abeta aggregates induced by zinc were reversible by chelation, but could then be reprecipitated by zinc for several cycles, indicating that the peptide's conformation is probably preserved in the zinc-mediated assembly. In contrast, Abeta aggregates induced by low pH (5.5) were not resolubilized by returning the pH milieu to 7.4. The zinc-Abeta interaction exhibits features resembling the gelation process of zinc-mediated fibrin assembly, suggesting that, in events such as clot formation or injury, reversible Abeta assembly could be physiologically purposive. Such a mechanism is contemplated in the early evolution of diffuse plaques in Alzheimer's disease and suggests a possible therapeutic strategy for the resolubilization of some forms of Abeta deposit in the disease.
Huang
X
X
Department of Psychiatry and the Genetics and Aging Unit, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Atwood
C S
CS
Moir
R D
RD
Hartshorn
M A
MA
Vonsattel
J P
JP
Tanzi
R E
RE
Bush
A I
AI
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000302:isolation & purification / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002850:Chromatography, Gel; D006801:Humans; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D015032:Zinc / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D015032:Zinc