Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.

ABSTRACT: Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn²⁺ induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC₅₀ value of 15 μm Importantly, at this concentration, Zn²⁺

SUBMITTER: Gerber H 

PROVIDER: S-EPMC5339758 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature