Short Aβ peptides attenuate Aβ42 toxicity in vivo

• Type of Material: Article
• Authors: Brenda D. Moore, University of Florida; Jason Martin, University of Florida; Lorena de Mena, University of Florida; Jonatan Sanchez, University of Florida; Pedro E. Cruz, University of Florida; Carolina Ceballos-Diaz, University of Florida; Thomas B. Ladd, University of Florida; Yong Ran, University of Florida; Yona Levites, University of Florida; Thomas Kukar, Emory University; Justin J. Kurian, University of Florida; Robert McKenna, University of Florida; Edward H. Koo, University of California San Diego; David R. Borchelt, University of Florida; Christopher Janus, University of Florida; Diego Rincon-Limas, University of Florida; Pedro Fernandez-Funez, University of Minnesota; Todd E. Golde, University of Florida
• Language: English
• Date: 2018-01-01
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Moore et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20170600
• Title of Journal or Parent Work: Journal of Experimental Medicine
• ISSN: 0022-1007
• Volume: 215
• Issue: 1
• Start Page: 283
• End Page: 301
• Grant/Funding Information: L. de Mena is a Howard Hughes Medical Institute fellow of the Life Sciences Research Foundation. J.J. Kurian is partially supported by an NIH T32 Basic Microbiology and Infectious Diseases Training Grant (5T32AI007110-34) managed by Dr. David Bloom at the University of Florida.; This research was supported by National Institutes of Health (NIH) grants U01AG046139, P50AG047266, R01AG18454, and P01AG020206.
• Keywords: FAMILIAL ALZHEIMERS-DISEASE; QUANTIFICATION; Life Sciences & Biomedicine; GAMMA-SECRETASE MODULATORS; Science & Technology; AMYLOID DEPOSITION; Immunology; NEUROTOXICITY; Medicine, Research & Experimental; Research & Experimental Medicine; TRANSGENIC MOUSE MODEL; TARGETED GENE-EXPRESSION; DROSOPHILA MODELS; BRICHOS; MICE
• Research Categories: Health Sciences, Pharmacology; Engineering, Biomedical

Abstract

Processing of amyloid-β (Aβ) precursor protein (APP) by γ-secretase produces multiple species of Aβ: Aβ40, short Aβ peptides (Aβ37-39), and longer Aβ peptides (Aβ42-43). γ-Secretase modulators, a class of Alzheimer's disease therapeutics, reduce production of the pathogenic Aβ42 but increase the relative abundance of short Aβ peptides. To evaluate the pathological relevance of these peptides, we expressed Aβ36-40 and Aβ42-43 in Drosophila melanogaster to evaluate inherent toxicity and potential modulatory effects on Aβ42 toxicity. In contrast to Aβ42, the short Aβ peptides were not toxic and, when coexpressed with Aβ42, were protective in a dose-dependent fashion. In parallel, we explored the effects of recombinant adeno- associated virus-mediated expression of Aβ38 and Aβ40 in mice. When expressed in nontransgenic mice at levels sufficient to drive Aβ42 deposition, Aβ38 and Aβ40 did not deposit or cause behavioral alterations. These studies indicate that treatments that lower Aβ42 by raising the levels of short Aβ peptides could attenuate the toxic effects of Aβ42.