The amyloid-β1-42-oligomer interacting peptide D-AIP possesses favorable biostability, pharmacokinetics, and brain region distribution

Adeola Shobo; Nicholas James; Daniel Dai; Alexander Röntgen; Corbin Black; Jean-Robert Kwizera; Mark A Hancock; Khanh Huy Bui; Gerhard Multhaup

doi:10.1016/j.jbc.2021.101483

The amyloid-β_1-42-oligomer interacting peptide D-AIP possesses favorable biostability, pharmacokinetics, and brain region distribution

J Biol Chem. 2022 Jan;298(1):101483. doi: 10.1016/j.jbc.2021.101483. Epub 2021 Dec 9.

Authors

Adeola Shobo¹, Nicholas James², Daniel Dai³, Alexander Röntgen⁴, Corbin Black³, Jean-Robert Kwizera¹, Mark A Hancock¹, Khanh Huy Bui³, Gerhard Multhaup⁵

Affiliations

¹ Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
² Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
³ Strathcona Anatomy Dentistry Building, McGill University, Montreal, Quebec, Canada.
⁴ Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Institute of Biochemistry, University of Cologne, Cologne, Germany.
⁵ Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada. Electronic address: Gerhard.multhaup@mcgill.ca.

Abstract

We have previously developed a unique 8-amino acid Aβ42 oligomer-Interacting Peptide (AIP) as a novel anti-amyloid strategy for the treatment of Alzheimer's disease. Our lead candidate has successfully progressed from test tubes (i.e., in vitro characterization of protease-resistant D-AIP) to transgenic flies (i.e., in vivo rescue of human Aβ42-mediated toxicity via D-AIP-supplemented food). In the present study, we examined D-AIP in terms of its stability in multiple biological matrices (i.e., ex-vivo mouse plasma, whole blood, and liver S9 fractions) using MALDI mass spectrometry, pharmacokinetics using a rapid and sensitive LC-MS method, and blood brain barrier (BBB) penetrance in WT C57LB/6 mice. D-AIP was found to be relatively stable over 3 h at 37 °C in all matrices tested. Finally, label-free MALDI imaging showed that orally administered D-AIP can readily penetrate the intact BBB in both male and female WT mice. Based upon the favorable stability, pharmacokinetics, and BBB penetration outcomes for orally administered D-AIP in WT mice, we then examined the effect of D-AIP on amyloid "seeding" in vitro (i.e., freshly monomerized versus preaggregated Aβ42). Complementary biophysical assays (ThT, TEM, and MALDI-TOF MS) showed that D-AIP can directly interact with synthetic Aβ42 aggregates to disrupt primary and/or secondary seeding events. Taken together, the unique mechanistic and desired therapeutic potential of our lead D-AIP candidate warrants further investigation, that is, testing of D-AIP efficacy on the altered amyloid/tau pathology in transgenic mouse models of Alzheimer's disease.

Keywords: Alzheimer disease; amyloid-beta oligomers; amyloid-beta42 peptide; amyloid-beta42-oligomer interacting peptide (AIP); anti-amyloid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides* / pharmacokinetics
Amyloid beta-Peptides* / pharmacology
Animals
Brain* / metabolism
Female
Male
Mice
Mice, Transgenic
Peptide Fragments* / pharmacokinetics
Peptide Fragments* / pharmacology

Substances

Amyloid beta-Peptides
Peptide Fragments
amyloid beta-protein (1-42)