TY - JOUR
T1 - Short Aβ peptides attenuate Aβ42 toxicity in vivo
AU - Moore, Brenda D.
AU - Martin, Jason
AU - de Mena, Lorena
AU - Sanchez, Jonatan
AU - Cruz, Pedro E.
AU - Ceballos-Diaz, Carolina
AU - Ladd, Thomas B.
AU - Ran, Yong
AU - Levites, Yona
AU - Kukar, Thomas L.
AU - Kurian, Justin J.
AU - McKenna, Robert
AU - Koo, Edward H.
AU - Borchelt, David R.
AU - Janus, Christopher
AU - Rincon-Limas, Diego
AU - Fernandez-Funez, Pedro
AU - Golde, Todd E.
N1 - Publisher Copyright:
© 2018 Moore et al.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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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U2 - 10.1084/jem.20170600
DO - 10.1084/jem.20170600
M3 - Article
C2 - 29208777
AN - SCOPUS:85039967555
SN - 0022-1007
VL - 215
SP - 283
EP - 301
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -