期刊
NEUROBIOLOGY OF DISEASE
卷 124, 期 -, 页码 36-45出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2018.10.021
关键词
Alzheimer's disease; Oral treatment; Amyloid beta (A beta) oligomers; D-enantiomeric peptides; Motor neurodegenerative phenotype; TBA2.1
资金
- Portfolio Technology and Medicine
- Helmholtz-Validierungsfonds of the Impuls and Vernetzungs-Fonds der Helmholtzgemeinschaft
- Portfolio Drug Research of the Impuls and Vernetzungs-Fonds der Helmholtzgemeinschaft
Alzheimer's disease, a multifactorial incurable disorder, is mainly characterised by progressive neurodegeneration, extracellular accumulation of amyloid-beta protein (A beta), and intracellular aggregation of hyperphosphorylated tau protein. During the last years, A beta oligomers have been claimed to be the disease causing agent. Consequently, development of compounds that are able to disrupt already existing A beta oligomers is highly desirable. We developed D-enantiomeric peptides, consisting solely of D-enantiomeric amino acid residues, for the direct and specific elimination of toxic A beta oligomers. The drug candidate RD2 did show high oligomer elimination efficacy in vitro and the in vivo efficacy of RD2 was demonstrated in treatment studies by enhanced cognition in transgenic mouse models of amyloidosis. Here, we report on the in vitro and in vivo efficacy of the compound towards pyroglutamate-A beta, a particular aggressive A beta species. Using the transgenic TBA2.1 mouse model, which develops pyroglutamate-A beta((3-42)) induced neurodegeneration, we are able to show that oral RD2 treatment resulted in a significant deceleration of the progression of the phenotype. The in vivo efficacy against this highly toxic A beta species further validates RD2 as a drug candidate for the therapeutic use in humans.
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