Short A beta peptides attenuate A beta 42 toxicity in vivo

Processing of amyloid-beta (A beta) precursor protein (APP) by gamma-secretase produces multiple species of A beta: A beta 40, short A beta peptides (A beta 37-39), and longer A beta peptides (A beta 42-43). gamma-Secretase modulators, a class of Alzheimer's disease therapeutics, reduce production of the pathogenic A beta 42 but increase the relative abundance of short A beta peptides. To evaluate the pathological relevance of these peptides, we expressed A beta 36-40 and A beta 42-43 in Drosophila melanogaster to evaluate inherent toxicity and potential modulatory effects on A beta 42 toxicity. In contrast to A beta 42, the short A beta peptides were not toxic and, when co-expressed with A beta 42, were protective in a dose-dependent fashion. In parallel, we explored the effects of recombinant adeno-associated virus-mediated expression of A beta 38 and A beta 40 in mice. When expressed in nontransgenic mice at levels sufficient to drive A beta 42 deposition, A beta 38 and A beta 40 did not deposit or cause behavioral alterations. These studies indicate that treatments that lower A beta 42 by raising the levels of short A beta peptides could attenuate the toxic effects of A beta 42.