Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion.
Zn(II) and Cu(II) precipitate Abeta in vitro into insoluble aggregates that are dissolved by metal chelators. We now report evidence that these biometals also mediate the deposition of Abeta amyloid in Alzheimer's disease, since the solubilization of Abeta from post-mortem brain tissue was significantly increased by the presence of chelators, EGTA, N,N,N',N'-tetrakis(2-pyridyl-methyl) ethylene diamine, and bathocuproine. Efficient extraction of Abeta also required Mg(II) and Ca(II). The chelators were more effective in extracting Abeta from Alzheimer's disease brain tissue than age-matched controls, suggesting that metal ions differentiate the chemical architecture of amyloid in Alzheimer's disease. Agents that specifically chelate copper and zinc ions but preserve Mg(II) and Ca(II) may be of therapeutic value in Alzheimer's disease.
Cherny
R A
RA
Department of Pathology, The University of Melbourne, Parkville, Victoria 3052, Australia.
Legg
J T
JT
McLean
C A
CA
Fairlie
D P
DP
Huang
X
X
Atwood
C S
CS
Beyreuther
K
K
Tanzi
R E
RE
Masters
C L
CL
Bush
A I
AI
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002614:Chelating Agents / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D004533:Egtazic Acid / Q000378:metabolism; D005029:Ethylenediamines / Q000378:metabolism; D006801:Humans; D010618:Phenanthrolines / Q000378:metabolism; D014867:Water; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D005029:Ethylenediamines; D010618:Phenanthrolines; D014867:Water; D004533:Egtazic Acid; D003300:Copper; C002478:bathocuproine; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine