Universität zu Köln

Shobo, Adeola ORCID: 0000-0002-2846-323X, James, Nicholas ORCID: 0000-0002-9939-4278, Dai, Daniel ORCID: 0000-0002-9973-0446, Roentgen, Alexander, Black, Corbin ORCID: 0000-0003-2777-6434, Kwizera, Jean-Robert, Hancock, Mark A., Bui, Khanh Huy ORCID: 0000-0003-2814-9889 and Multhaup, Gerhard (2022). The amyloid-beta(1-42)-oligomer interacting peptide D-AIP possesses favorable biostability, pharmacokinetics, and brain region distribution. J. Biol. Chem., 298 (1). AMSTERDAM: ELSEVIER. ISSN 1083-351X

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Abstract

We have previously developed a unique 8-amino acid A beta 42 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 A beta 42-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. DAIP was found to be relatively stable over 3 h at 37 degrees 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 A beta 42). Complementary biophysical assays (ThT, TEM, and MALDI-TOF MS) showed that D-AIP can directly interact with synthetic A beta 42 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Shobo, Adeola UNSPECIFIED orcid.org/0000-0002-2846-323X UNSPECIFIED James, Nicholas UNSPECIFIED orcid.org/0000-0002-9939-4278 UNSPECIFIED Dai, Daniel UNSPECIFIED orcid.org/0000-0002-9973-0446 UNSPECIFIED Roentgen, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Black, Corbin UNSPECIFIED orcid.org/0000-0003-2777-6434 UNSPECIFIED Kwizera, Jean-Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Hancock, Mark A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bui, Khanh Huy UNSPECIFIED orcid.org/0000-0003-2814-9889 UNSPECIFIED Multhaup, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-665663
DOI:	10.1016/j.jbc.2021.101483
Journal or Publication Title:	J. Biol. Chem.
Volume:	298
Number:	1
Date:	2022
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language D-AMINO-ACID; ALZHEIMERS-DISEASE; TOXICITY; OLIGOMERS; METABOLISM; MECHANISM; PATHOLOGY; SEEDS Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66566