Journal
ACS CHEMICAL NEUROSCIENCE
Volume 1, Issue 9, Pages 639-648Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cn100057j
Keywords
Mirror image phage display; D-enantiomeric peptide; Alzheimer's disease; oligomers; drugs
Funding
- Volkswagen-Stiftung [I/82 649]
- Prasidentenfond der Helmholtzgemeinschaft (HGF, Virtual Institute of Structural Biology)
- DGCIS grant (French state)
- [P30 NS47466]
- [5P50 AG16582-10]
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Several lines of evidence suggest that the amyloid-beta-peptide (A beta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Not only A beta fibrils but also small soluble A beta oligomers in particular are suspected to be the major toxic species responsible for disease development and progression. The present study reports on in vitro and in vivo properties of the A beta targeting D-enantiomeric amino acid peptide D3. We show that next to plaque load and inflammation reduction, oral application of the peptide improved the cognitive performance of AD transgenic mice. In addition, we provide in vitro data elucidating the potential mechanism underlying the observed in vivo activity of D3. These data suggest that D3 precipitates toxic A beta species and converts them into nonamyloidogenic, nonfibrillar, and nontoxic aggregates without increasing the concentration of monomeric A beta. Thus, D3 exerts an interesting and novel mechanism of action that abolishes toxic A beta oligomers and thereby supports their decisive role in AD development and progression.
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