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

Catherine F. Roberts, Yiwei Cao, Wonpil Im, Robert A. Nichols, Ronald J. Lukas, Andrew A. George

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Purpose: Oligomeric amyloid β 1-42 (oAβ1-42) exhibits agonist-like action at human α7- and α7β2-containing nicotinic receptors. The N-terminal amyloid β1-15 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 oAβ1-42-associated synapto- and neurotoxicity. Here, we investigated how oAβ1-42, 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, oAβ1-42, 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, oAβ1-42 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 oAβ1-42, selectively enhanced α7-nicotinic receptor open probability and open-dwell times (compared to acetylcholine or oAβ1-42). 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 oAβ1-42.

Original languageEnglish
JournalBritish Journal of Pharmacology
Early online date8 May 2024
DOIs
Publication statusE-pub ahead of print - 8 May 2024
Externally publishedYes

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions

Acknowledgements

We thank Dr. Paul Whiteaker and Dana Kneisley for their critical feedback on the manuscript.

Keywords

  • Alzheimer's disease
  • amyloid
  • concatemers
  • nicotinic receptors
  • single-channel

ASJC Scopus subject areas

  • Pharmacology

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