Abstract
Alzheimer’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.
Highlights
Alzheimer’s disease (AD) is known to be the most common form of dementia worldwide. the detailed reasons for the development of the disease are still not fully understood, major pathological hallmarks of this disease are extracellular amyloid β protein (Aβ) accumulations, neurofibrillary tangles of the hyperphosphorylated protein tau, neuroinflammation, and neurodegeneration, all together resulting in cognitive decline of the affected patients
We have already proven that RD2 and D3D3 were able to eliminate Aβ(1–42) oligomers significantly more efficiently than the lead compound D3 [8,16]
D3-derivatives RD2RD2 and RD2D3 regarding their Aβ oligomer eliminating abilities was investigated in vitro by performance of a quantitative determination of interference with the Aβ aggregate size distribution (Aβ QIAD) assay. Findings of this analysis demonstrate that RD2RD2 and RD2D3 significantly and efficiently eliminated toxic Aβ(1–42) oligomers (Figure 1A)
Summary
Alzheimer’s disease (AD) is known to be the most common form of dementia worldwide. the detailed reasons for the development of the disease are still not fully understood, major pathological hallmarks of this disease are extracellular amyloid β protein (Aβ) accumulations (plaques), neurofibrillary tangles of the hyperphosphorylated protein tau, neuroinflammation, and neurodegeneration, all together resulting in cognitive decline of the affected patients. We pursued a different approach by rationally designing new D3-derivatives to increase knowledge in regard to essential sequence motifs and to increase efficacy In this context, we identified four compounds with very promising in vitro properties, especially regarding their efficiency in Aβ oligomer elimination. We identified four compounds with very promising in vitro properties, especially regarding their efficiency in Aβ oligomer elimination Those include “RD2”, which consists of exactly the same amino acid residues as D3 but in a re-arranged sequence; “D3D3” and “RD2RD2”, the head-to-tail linear connected homodimers of the lead compounds D3 and RD2, respectively; as well as the head-to-tail linear connected heterodimer of RD2 and D3, termed “RD2D3”. The cognitive deficit of APPSL mice was completely reversed and learning abilities of both treatment groups were similar to those of non-transgenic littermates
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