Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid

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 (2 μM) 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.