Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid

Abstract 

Abnormal interaction of β-amyloid 42 (Aβ42) with copper, zinc and iron induce peptide aggregation and oxidation in Alzheimer's disease (AD). However, in health, Aβ degradation is mediated by extracellular metalloproteinases, neprilysin, insulin degrading enzyme (IDE) and matrix metalloproteinases. We investigated the relationship between levels of Aβ and biological metals in CSF. We assayed CSF copper, zinc, other metals and Aβ42 in ventricular autopsy samples of Japanese American men (N=131) from the population-based Honolulu Asia Aging Study. There was a significant inverse correlation of CSF Aβ42 with copper, zinc, iron, manganese and chromium. The association was particularly strong in the subgroup with high levels of both zinc and copper. Selenium and aluminum levels were not associated to CSF Aβ42. In vitro, the degradation of synthetic Aβ substrate added to CSF was markedly accelerated by low levels (2μM) of exogenous zinc and copper. While excessive interaction with copper and zinc may induce neocortical Aβ precipitation in AD, soluble Aβ degradation is normally promoted by physiological copper and zinc concentrations.

Abbreviations: Aβ42, β-amyloid ending at residue 42, AD, Alzheimer's disease, APP, amyloid protein precursor, APLP2, amyloid precursor-like protein 2, CAA, congophilic amyloid angiopathy, CERAD, consortium to establish a registry for Alzheimer's disease, CI, confidence interval, CQ, clioquinol, CSF, cerebrospinal fluid, ELISA, enzyme-linked immunosorbent assay, GLM, general linear regression model, NFT, neurofibrillary tangle, NP, neuritic plaque, PMI, post-mortem interval, SOD1, superoxide dismutase 1, TPEN, N,N,N′,N′-Tetrakis-(2-pyridylmethyl)-ethylenediamine, MMP, matrix metalloproteinase, SDS, sodium dodecyl sulfate

Keywords: Amyloid, Alzheimer's disease, Metalloproteinase, Cerebrospinal fluid, Zinc, Copper, Iron, Manganese, Chromium