Nicholas James, Canada
McGill University Integrated Program in NeuroscienceAuthor Of 1 Presentation
METABOLIC STABILITY OF ABETA42-OLIGOMER INTERACTING PEPTIDES (AIP) AND MECHANISMS OF THEIR ANTI-AMYLOID ACTIVITY
Abstract
Aims
We have developed a unique 8-amino acid Abeta42-oligomer Interacting Peptide (AIP) as a novel anti-amyloid strategy against Alzheimer disease (AD). Our lead candidate has successfully advanced from test tubes (in vitro characterization of AIP) to flies (in vivo rescue of human Abeta42-mediated toxicity via AIP-supplemented food) (Barucker 2015, Zhong 2019). Further, we validated the drug candidate AIP, i.e. testing the stability in multiple biological matrices (i.e. mouse whole blood, plasma, and liver S9 fractions) and if AIP could penetrate the blood brain barrier (BBB) of C57BL/6 (wildtype) mice.
Methods
The stability and possible degradation of the AIP was qualitatively assessed by MALDI mass spectrometry. MALDI imaging data confirmed that orally-administered AIP penetrated the BBB of both male and female wildtype mice.
Results
AIP was relatively stable over 3 hours in whole blood and in S9 liver fractions. AIP could cross the BBB of male and female wildtype mice using both intraperitoneal and oral delivery strategies. Thus, our AIP is significantly more stable compared to protease-sensitive peptides which implies its potential use as an orally administrable drug candidate against AD.
Conclusions
Based upon the unique ability of AIP to “trap” and neutralize toxic Abeta42 oligomers and the stability of AIP, AIP efficacy is currently being tested in mouse models of AD towards behavioral impairments, age-associated cognitive deficits and amyloid and/or tau pathologies.