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Neuroprotective amyloid-beta N-terminal peptides differentially alter human α7- and α7β2-nicotinic acetylcholine receptor single-channel properties
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  • Catherine Roberts,
  • Yiwei Cao,
  • Wonpil Im,
  • Robert Nichols,
  • Ronald Lukas,
  • Andrew George
Catherine Roberts
University of Bath
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Yiwei Cao
Lehigh University
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Wonpil Im
Lehigh University
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Robert Nichols
University of Hawai'i at Manoa
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Ronald Lukas
Barrow Neurological Institute
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Andrew George
Virginia Commonwealth University

Corresponding Author:[email protected]

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Abstract

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.
16 Oct 2023Submitted to British Journal of Pharmacology
24 Oct 2023Assigned to Editor
24 Oct 2023Submission Checks Completed
24 Oct 2023Review(s) Completed, Editorial Evaluation Pending
25 Oct 2023Reviewer(s) Assigned