Toxicity Mechanism of Aβ42 Oligomer in the Binding between the GABABR1a sushi1 Domain and Amyloid Precursor Protein 9mer: A Mechanism like Substitution Reaction.

Abstract

Amyloid-β peptide (Aβ), characterized by its abnormal folding into neurotoxic aggregates, impairs synaptic plasticity and causes synaptic loss associated with Alzheimer's disease (AD). The neurotoxicity of Aβ oligomers via the binding to various cell-surface receptors was frequently observed experimentally; however, the toxic mechanism still remains unknown. In this paper, we study the intervention of Aβ oligomers to the receptor-peptide binding in the GABABR1a sushi1-APP 9mer complex, a key node in increasing short-term synaptic facilitation in the mouse hippocampus and decreasing neuronal activity by inhibiting neurotransmitter release by molecular dynamics simulations. The residue types of Aβ42 oligomers involved in the intervention and core contact areas of the receptor were first identified, by which an unprecedented toxicity mechanism of Aβ42 oligomers is proposed. These involved residues of Aβ42 oligomers are positively charged residues Asp and Glu, and the core area of GABABR1a sushi1 domain is the Coil one, sharing the rich negatively charged residues R19/R21/R25/R45 with the pocket, in which APP 9mer is locked. The presence of an Aβ42 oligomer rather than of a monomer stretches these key residues in the core area and consequently "unlocks and releases" the APP 9mer from its initial pocket, unsteadying the sushi1 domain and taking into toxic effect. It looks like a chemical "substitution" reaction, Aβ42 oligomer + GABABR1a sushi1-APP 9mer complex → Aβ42 oligomer-GABABR1a sushi1 complex + APP 9mer. Further analysis reveals that the toxicity of Aβ42 oligomer to GABABR1a sushi1 domain stability depends on the residue number of the contact area and the size of Aβ42 oligomer, in which semi-extended trimeric Aβ42 oligomer is identified as the most toxic one. This work provides a novel insight into the mechanism of Aβ oligomeric toxicity to neuroreceptors and sets an important precedent for dealing with Aβ oligomeric toxicity to other receptors at the molecular level.