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+ also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 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 Aβ production, whereas the increased Aβ43:Aβ40 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 Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD.
Highlights
Increased intracellular copper or zinc has been linked to a reduction in secreted levels of the Alzheimer’s disease (AD)-causing amyloid- peptide (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 amyloid precursor protein (APP)-C99
APP-C83 is further processed by ␥-secretase to generate the peptides p3 of largely unknown functions, ␥-secretase processing of APP-C99 led to the generation of soluble A peptides forming the toxic oligomers, fibrils, and plaques implicated in the pathogenesis of Alzheimer’s disease (Fig. 1A)
Summary
Increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid- peptide (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. 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. Different cell-based and cell-free studies have demonstrated that Cu2ϩ and Zn2ϩ bind A peptides and the amyloid precursor protein (APP) with high affinity (10 –12) and are involved in the aggregation or fibrillization of A [10, 13]. The elevation of intracellular Cu2ϩ or Zn2ϩ levels by genetic or pharmacological methods in different cellular and in vivo systems have consistently been shown to attenuate the pro-
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