Abstract

Formation of toxic aggregates and plaques consisting of beta-amyloid (Aβ) peptides is a generally acknowledged early event in Alzheimer’s Disease. This fact prompted the development of numerous therapies focusing on inhibition of Aβ synthesis or dissolution of Aβ-derived structures. These therapies do not work, and it seems that Aβ elimination is as detrimental to brain function as its excess. A distinct line of research connects mechanisms of Aβ toxicity with copper physiology, postulating the Cu(Aβ) complexes as important toxic species acting via oxidative stress.

We revisited the Aβ/copper relationship taking into account sequence heterogeneity of this family of peptides. Our studies resulted in a proposal of physiological function for Aβ4-x peptide subfamily as synaptic copper scavengers and shuttles. This concept helps explain the failures of Aβ-directed therapeutic approaches, set limits on applicability of chelation therapies in neurodegenerative diseases and assist development of novel ideas in AD treatment.