Oral Treatment with the d-Enantiomeric Peptide D3 Improves the Pathology and Behavior of Alzheimer’s Disease Transgenic Mice

Abstract

)Heinrich-Heine-Universit€ at D€ usseldorf, Institut f€ ur Physikalische Biologie and BMFZ, 40225 D€ usseldorf, Germany,^Forschungszentrum J€ ulich, ISB-2, 52425 J€ ulich AbstractSeveral lines of evidence suggest that the amyloid-β-peptide (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Not only Aβ fibrils but also small soluble Aβ 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 Aβ 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 Aβ species and converts them into nonamyloidogenic, nonfibrillar, and nontoxic aggregates without increasing the concentration of monomeric Aβ. Thus, D3 exerts an interesting and novel mechanism of action that abolishes toxic Aβ oligomers and thereby supports their decisive role in AD development and progression.

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

“…The substitution of all-D-amino-acids for the peptide segment may be one of approaches. The potency of all-D-amino-acids as inhibitor against fibril formation has been confirmed by the investigations of Ab peptides [34][35][36]. Moreover, the all-D-amino-acid inhibitors are resistant to proteolytic degradation [37,38] and usually less immunogenic [39].…”

D-amino acid-based peptide inhibitors as early or preventative therapy in Alzheimer disease

“…They observed labeled monomers interacting with unlabelled oligomers and protofibrils. They determined that Aβ sequences LVFFA (17)(18)(19)(20)(21), AII (30)(31)(32), LMV (34)(35)(36), and VVIA (39)(40)(41)(42) were the initial contact points between Aβ monomers and oligomers (Fig. 2).…”

The Functions of the Amyloid Precursor Protein Gene and Its Derivative Peptides: II Experimental Evidence and Clinical Studies

“…This experimental study suggests that Aβ oligomers affect synaptic function, the processing of presynaptic proteins and of the microtubular associated protein tau [269]. An oral compound Denantiometric peptide D3 has been shown to improve the cognitive performance of AD transgenic mice probably by binding Aβ oligomers and converting them to nonamyloidogenic, non-fibrillar and non-toxic aggregates without increasing the concentration of mononeuric Aβ [270].…”