Short Aβ peptides attenuate Aβ42 toxicity in vivo

Brenda D. Moore, Jason Martin, Lorena de Mena, Jonatan Sanchez, Pedro E. Cruz, Carolina Ceballos-Diaz, Thomas B. Ladd, Yong Ran, Yona Levites, Thomas L. Kukar, Justin J. Kurian, Robert McKenna, Edward H. Koo, David R. Borchelt, Christopher Janus, Diego Rincon-Limas, Pedro Fernandez-Funez, Todd E. Golde

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)283-301
Number of pages19
JournalJournal of Experimental Medicine
Volume215
Issue number1
DOIs
StatePublished - Jan 1 2018

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Peptides
Serum Amyloid A Protein
Amyloid Precursor Protein Secretases
Poisons
Dependovirus
Drosophila melanogaster
Alzheimer Disease
peptide A42
Therapeutics

Cite this

Moore, B. D., Martin, J., de Mena, L., Sanchez, J., Cruz, P. E., Ceballos-Diaz, C., ... Golde, T. E. (2018). Short Aβ peptides attenuate Aβ42 toxicity in vivo. Journal of Experimental Medicine, 215(1), 283-301. https://doi.org/10.1084/jem.20170600

Short Aβ peptides attenuate Aβ42 toxicity in vivo. / 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.

In: Journal of Experimental Medicine, Vol. 215, No. 1, 01.01.2018, p. 283-301.

Research output: Contribution to journalArticle

Moore, BD, Martin, J, de Mena, L, Sanchez, J, Cruz, PE, Ceballos-Diaz, C, Ladd, TB, Ran, Y, Levites, Y, Kukar, TL, Kurian, JJ, McKenna, R, Koo, EH, Borchelt, DR, Janus, C, Rincon-Limas, D, Fernandez-Funez, P & Golde, TE 2018, 'Short Aβ peptides attenuate Aβ42 toxicity in vivo', Journal of Experimental Medicine, vol. 215, no. 1, pp. 283-301. https://doi.org/10.1084/jem.20170600
Moore BD, Martin J, de Mena L, Sanchez J, Cruz PE, Ceballos-Diaz C et al. Short Aβ peptides attenuate Aβ42 toxicity in vivo. Journal of Experimental Medicine. 2018 Jan 1;215(1):283-301. https://doi.org/10.1084/jem.20170600
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. / Short Aβ peptides attenuate Aβ42 toxicity in vivo. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 1. pp. 283-301.
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