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J Exp Med. 2018 Jan 2;215(1):283-301. doi: 10.1084/jem.20170600. Epub 2017 Dec 5.

Short Aβ peptides attenuate Aβ42 toxicity in vivo.

Author information

1
Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL.
2
McKnight Brain Institute, University of Florida, Gainesville, FL.
3
Department of Neurology, University of Florida, Gainesville, FL.
4
Department of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, GA.
5
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL.
6
Department of Neuroscience, University of California, San Diego, La Jolla, CA.
7
Department of Biomedical Sciences, University of Minnesota School of Medicine, Duluth, MN.
8
Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL tgolde@mbi.ufl.edu.

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.

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