The structure of tyrosine-10 favors ionic conductance of Alzheimer's disease-associated full-length amyloid-β channels

Abhijith G Karkisaval; Rowan Hassan; Andrew Nguyen; Benjamin Balster; Faisal Abedin; Ratnesh Lal; Suren A Tatulian

doi:10.1038/s41467-023-43821-y

The structure of tyrosine-10 favors ionic conductance of Alzheimer's disease-associated full-length amyloid-β channels

Nat Commun. 2024 Feb 13;15(1):1296. doi: 10.1038/s41467-023-43821-y.

Authors

Abhijith G Karkisaval¹, Rowan Hassan², Andrew Nguyen³, Benjamin Balster³, Faisal Abedin^{2

4}, Ratnesh Lal^{5

6}, Suren A Tatulian⁷

Affiliations

¹ Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA.
² Department of Physics, University of Central Florida, Orlando, FL, USA.
³ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
⁴ Department of Biology, Xavier University of Louisiana, New Orleans, LA, USA.
⁵ Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA. rlal@ucsd.edu.
⁶ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. rlal@ucsd.edu.
⁷ Department of Physics, University of Central Florida, Orlando, FL, USA. statulia@ucf.edu.

Abstract

Amyloid β (Aβ) ion channels destabilize cellular ionic homeostasis, which contributes to neurotoxicity in Alzheimer's disease. The relative roles of various Aβ isoforms are poorly understood. We use bilayer electrophysiology, AFM imaging, circular dichroism, FTIR and fluorescence spectroscopy to characterize channel activities of four most prevalent Aβ peptides, Aβ_1-42, Aβ_1-40, and their pyroglutamylated forms (AβpE_3-42, AβpE_3-40) and correlate them with the peptides' structural features. Solvent-induced fluorescence splitting of tyrosine-10 is discovered and used to assess the sequestration from the solvent and membrane insertion. Aβ_1-42 effectively embeds in lipid membranes, contains large fraction of β-sheet in a β-barrel-like structure, forms multi-subunit pores in membranes, and displays well-defined ion channel features. In contrast, the other peptides are partially solvent-exposed, contain minimal β-sheet structure, form less-ordered assemblies, and produce irregular ionic currents. These findings illuminate the structural basis of Aβ neurotoxicity through membrane permeabilization and may help develop therapies that target Aβ-membrane interactions.

MeSH terms

Alzheimer Disease*
Amyloid beta-Peptides* / metabolism
Humans
Ion Channels / chemistry
Peptide Fragments / metabolism
Solvents
Tyrosine

Substances

Amyloid beta-Peptides
Tyrosine
Ion Channels
Solvents
Peptide Fragments

Grants and funding

21A06/Florida Department of Health