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000838455 1001_ $$0P:(DE-Juel1)159137$$aKutzsche, Janine$$b0$$ufzj
000838455 245__ $$aLarge-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer’s Disease
000838455 260__ $$aBasel$$bMDPI$$c2017
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000838455 520__ $$aAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development. Our therapeutic approach aims at specific and direct elimination of toxic Aβ oligomers by stabilizing Aβ monomers in an aggregation-incompetent conformation. We have proven that our lead compound “D3”, an all d-enantiomeric-peptide, specifically eliminates Aβ oligomers in vitro. In vivo, D3 enhances cognition and reduces plaque load in several transgenic AD mouse models. Here, we performed a large-scale oral proof of concept efficacy study, in which we directly compared four of the most promising D3-derivatives in transgenic mice expressing human amyloid precursor protein with Swedish and London mutations (APPSL), transgenic mice, to identify the most effective compound. RD2 and D3D3, both derived from D3 by rational design, were discovered to be the most effective derivatives in improving cognition in the Morris water maze. The performance of RD2- and D3D3-treated mice within the Morris water maze was significantly better than placebo-treated mice and, importantly, nearly as good as those of non-transgenic littermates, suggesting a complete reversal of the cognitive deficit of APPSL mice.
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000838455 7001_ $$0P:(DE-Juel1)165908$$aSchemmert, Sarah$$b1$$ufzj
000838455 7001_ $$0P:(DE-Juel1)131709$$aTusche, Markus$$b2$$ufzj
000838455 7001_ $$0P:(DE-HGF)0$$aNeddens, J.$$b3
000838455 7001_ $$0P:(DE-HGF)0$$aRabl, R.$$b4
000838455 7001_ $$0P:(DE-Juel1)144626$$aJürgens, Dagmar$$b5$$ufzj
000838455 7001_ $$0P:(DE-HGF)0$$aBrener, O.$$b6
000838455 7001_ $$0P:(DE-Juel1)144347$$aWilluweit, Antje$$b7$$ufzj
000838455 7001_ $$0P:(DE-HGF)0$$aHutter-Paier, B.$$b8
000838455 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b9$$eCorresponding author$$ufzj
000838455 773__ $$0PERI:(DE-600)2008644-1$$a10.3390/molecules22101693$$p1693$$tMolecules$$v22$$x1420-3049$$y2017
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