Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by ?-Secretase and Amyloid-? 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-? peptide (A?). However, little is known about whether these biometals modulate the generation of A?. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate A? production by distinct molecular mechanisms affecting the processing by ?-secretase of its A? precursor protein substrate APP-C99. We found that Zn²⁺ induces APP-C99 dimerization, which prevents its cleavage by ?-secretase and A? production, with an IC₅₀ value of 15 ?m Importantly, at this concentration, Zn²⁺ also drastically raised the production of the aggregation-prone A?43 found in the senile plaques of AD brains and elevated the A?43:A?40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn²⁺-dependent APP-C99 dimerization and inhibition of A? production, whereas the increased A?43:A?40 ratio is substrate dimerization-independent and involves the known Zn²⁺ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited A? production by directly targeting the subunits presenilin and nicastrin in the ?-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate A? production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic A? species, may offer two therapeutic strategies for preventing AD.

SUBMITTER: Gerber H 

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

REPOSITORIES: biostudies-literature