Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide.
A major pathological feature of Alzheimer's disease (AD) is the presence of a high density of amyloid plaques in the brain tissue of patients. The plaques are predominantly composed of human beta-amyloid peptide beta A4, a 40-mer whose neurotoxicity is related to its aggregation. Certain metals have been proposed as risk factors for AD, but the mechanism by which the metals may exert their effects is unclear. Radioiodinated human beta A4 has been used to assess the effects of various metals on the aggregation of the peptide in dilute solution (10(-10) M). In physiological buffers, 10(-3) M calcium, cobalt, copper, manganese, magnesium, sodium, or potassium had no effect on the rate of beta A4 aggregation. In sharp contrast, aluminum, iron, and zinc under the same conditions strongly promoted aggregation (rate enhancement of 100-1,000-fold). The aggregation of beta A4 induced by aluminum and iron is distinguishable from that induced by zinc in terms of rate, extent, pH and temperature dependence. These results suggest that high concentrations of certain metals may play a role in the pathogenesis of AD by promoting aggregation of beta A4.
Mantyh
P W
PW
Molecular Neurobiology Laboratory (151), Veteran's Administration Medical Center, Minneapolis, Minnesota 55417.
Ghilardi
J R
JR
Rogers
S
S
DeMaster
E
E
Allen
C J
CJ
Stimson
E R
ER
Maggio
J E
JE
D000535:Aluminum / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007477:Ions; D007501:Iron / Q000494:pharmacology*; D009994:Osmolar Concentration; D015032:Zinc / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D007477:Ions; D000535:Aluminum; D007501:Iron; D015032:Zinc