Neuroprotective amyloid-beta N-terminal peptides differentially alter human α7- and α7β2-nicotinic acetylcholine receptor single-channel properties

Background: and Purpose: Oligomeric Aβ1-42 (oAβ42) exhibits agonist-like action at human α7- and α7β2-nicotinic receptors (collectively, α7*-nAChR). Aβ1-42 and an N-terminal Aβ peptide fragment (N-Aβ fragment: Aβ1-15/16) have been shown to modulate presynaptic Ca2+ and enhance hippocampus-based synaptic plasticity via α7* nAChR. Both the N-Aβ fragment and its essential core sequence, the N-Aβcore hexapeptide (Aβ10-15), protect against Aβ-associated synapto- and neurotoxicity, also involving nAChR. Here, we investigated how oAβ42, the N-Aβ fragment and N-Aβcore regulate the functional activity of α7*-nAChRs. Experimental approach: Single-channel patch clamp recordings measured the impact of ACh, oAβ42, the N-Aβ fragment, and the N-Aβcore on the function of concatenated, human α7- and α7β2-containing nAChR expressed in nAChR-null SH-EP1 cells. Molecular dynamics simulations identified potential sites of interaction between the N-Aβ fragment and the orthosteric α7*-nAChR binding interfaces. Key Results: Relative to the effects of ACh alone, oAβ42 preferentially enhanced α7β2-nAChR open probability and open-dwell times. Co-application with the N-Aβcore neutralized these effects. Further, we demonstrate that the N-Aβ fragment alone, or in combination with ACh or oAβ42, resulted in selective enhancement of α7-nAChR single-channel open probability and open-dwell times (compared to ACh or oAβ42). Conclusions and Implications: Our findings show the functional diversity of Aβ peptides in regulating α7*-nAChR function, with implications for a wide range of nAChR-mediated functions in AD. Single-channel recordings of the differential effects of oAβ42, N-Aβ fragment and/or N-Aβcore on α7*-nAChR isoform function revealed the complexities of their interactions with α7*-nAChR, with new insights into the neuroprotective actions of these N-Aβ-derived peptides.