Neuroprotective amyloid β N-terminal peptides differentially alter human α7- and α7β2-nicotinic acetylcholine (nACh) receptor single-channel properties.

Background and Purpose: Oligomeric amyloid β _1-42 (oAβ _1-42 ) exhibits agonist-like action at human α7- and α7β2-containing nicotinic receptors. The N-terminal amyloid β _1-15 fragment (N-Aβ fragment) modulates presynaptic calcium and enhances hippocampal-based synaptic plasticity via α7-containing nicotinic receptors. Further, the N-Aβ fragment and its core sequence, the N-amyloid-beta core hexapeptide (N-Aβcore), protect against oAβ _1-42 -associated synapto- and neurotoxicity. Here, we investigated how oAβ _1-42 , the N-Aβ fragment, and the N-Aβcore regulate the single-channel properties of α7- and α7β2-nicotinic receptors.
Experimental Approach: Single-channel recordings measured the impact of acetylcholine, oAβ _1-42 , the N-Aβ fragment, and the N-Aβcore on the unitary properties of human α7- and α7β2-containing nicotinic receptors expressed in nicotinic-null SH-EP1 cells. Molecular dynamics simulations identified potential sites of interaction between the N-Aβ fragment and orthosteric α7+/α7- and α7+/β2- nicotinic receptor binding interfaces.
Key Results: The N-Aβ fragment and N-Aβcore induced α7- and α7β2-nicotinic receptor single-channel openings. Relative to acetylcholine, oAβ _1-42 preferentially enhanced α7β2-nicotinic receptor single-channel open probability and open-dwell times. Co-application with the N-Aβcore neutralized these effects. Further, administration of the N-Aβ fragment alone, or in combination with acetylcholine or oAβ _1-42 , selectively enhanced α7-nicotinic receptor open probability and open-dwell times (compared to acetylcholine or oAβ _1-42 ).
Conclusions and Implications: Amyloid-beta peptides demonstrate functional diversity in regulating α7- and α7β2-nicotinic receptor function, with implications for a wide range of nicotinic receptor-mediated functions in Alzheimer's disease. The effects of these peptides on α7- and/or α7β2-nicotinic receptors revealed complex interactions with these subtypes, providing novel insights into the neuroprotective actions of amyloid β-derived fragments against the toxic effects of oAβ _1-42 .
(© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)