Zinc-binding site of Amyloid-beta peptide (Zn-Aβ interface)

The zinc-binding site of the amyloid-beta (Aβ) peptide is a critical structural interface involved in the pathogenesis of Alzheimer's disease (Bush, 2003, PMID: 12849660). Zinc ions (Zn2+) interact primarily with the N-terminal region of Aβ, specifically coordinating with histidine residues at positions 6, 13, and 14 (Miller et al., 2010, PMID: 20816919). This interaction promotes the rapid, non-fibrillar aggregation of Aβ into neurotoxic oligomers and insoluble plaques, which are hallmarks of neurodegeneration (Fallon et al., 2021, PMID: 34203456). Furthermore, the sequestration of zinc by Aβ plaques leads to a localized deficiency of synaptic zinc, impairing neurotransmission and cognitive function. Therapeutic strategies targeting this interface include metal-protein attenuating compounds (MPACs) like PBT2, which aim to disrupt the Aβ-zinc complex (Adlard et al., 2008, PMID: 18631024). These drugs work by preventing metal-induced aggregation and facilitating the re-uptake of zinc into neurons, thereby restoring metal homeostasis and reducing amyloid burden.

Other names

Zinc-amyloid beta complexAβ-Zn2+ binding siteMetal-binding domain of Amyloid-betaZinc-Aβ interface

Metal-protein attenuation, inhibition of amyloid-beta aggregation, and redistribution of metal ions from the extracellular space into neurons.