Short Aβ peptides attenuate Aβ42 toxicity in vivo

• Published in: The Journal of experimental medicine Vol. 215; no. 1; pp. 283 - 301
• Main Authors: Moore, Brenda D, Martin, Jason, de Mena, Lorena, Sanchez, Jonatan, Cruz, Pedro E, Ceballos-Diaz, Carolina, Ladd, Thomas B, Ran, Yong, Levites, Yona, Kukar, Thomas L, Kurian, Justin J, McKenna, Robert, Koo, Edward H, Borchelt, David R, Janus, Christopher, Rincon-Limas, Diego, Fernandez-Funez, Pedro, Golde, Todd E
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02-01-2018; The Rockefeller University Press
• Subjects: Amyloid - genetics; Amyloid - metabolism; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - genetics; Amyloid precursor protein; Animals; Animals, Genetically Modified; Biocompatibility; Brain - metabolism; Brain - pathology; Drosophila melanogaster; Eye - metabolism; Eye - pathology; Eye - ultrastructure; Female; Fruit flies; Locomotion; Mice; Mice, Transgenic; Modulators; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptide Fragments - toxicity; Peptides; Phenotype; Protein Aggregates; Protein Aggregation, Pathological - metabolism; Relative abundance; Secretase; Toxicity; Viruses
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20170600

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
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.