The Aβ oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology

Groen, Thomas van; Schemmert, Sarah; Brener, Oleksandr; Gremer, Lothar; Ziehm, Tamar; Tusche, Markus; Nagel-Steger, Luitgard; Kadish, Inga; Schartmann, Elena; Elfgen, Anne; Jürgens, Dagmar; Willuweit, Antje; Kutzsche, Janine; Willbold, Dieter

doi:10.1038/s41598-017-16565-1

Cited by 43 publications

(64 citation statements)

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“…For A␤(1-42)directed D-peptides, high stability in media simulating the route of orally administered drugs (33) and enhanced proteolytic stability in murine plasma and organ homogenates were shown (34). The lead compound of these D-peptides, D3, had been selected by mirror-image phage display (26,35). D3 and its tandem version, D3D3, convert toxic A␤ species into nontoxic species (25,28).…”

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confidence: 99%

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

Rösener

Gremer

Reinartz

et al. 2018

Journal of Biological Chemistry

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. One AD hallmark is the aggregation of β-amyloid (Aβ) into soluble oligomers and insoluble fibrils. Several studies have reported that oligomers rather than fibrils are the most toxic species in AD progression. Aβ oligomers bind with high affinity to membrane-associated prion protein (PrP), leading to toxic signaling across the cell membrane, which makes the Aβ-PrP interaction an attractive therapeutic target. Here, probing this interaction in more detail, we found that both full-length, soluble human (hu) PrP(23-230) and huPrP(23-144), lacking the globular C-terminal domain, bind to Aβ oligomers to form large complexes above the megadalton size range. Following purification by sucrose density-gradient ultracentrifugation, the Aβ and huPrP contents in these heteroassemblies were quantified by reversed-phase HPLC. The Aβ:PrP molar ratio in these assemblies exhibited some limited variation depending on the molar ratio of the initial mixture. Specifically, a molar ratio of about four Aβ to one huPrP in the presence of an excess of huPrP(23-230) or huPrP(23-144) suggested that four Aβ units are required to form one huPrP-binding site. Of note, an Aβ-binding all-d-enantiomeric peptide, RD2D3, competed with huPrP for Aβ oligomers and interfered with Aβ-PrP heteroassembly in a concentration-dependent manner. Our results highlight the importance of multivalent epitopes on Aβ oligomers for Aβ-PrP interactions and have yielded an all-d-peptide-based, therapeutically promising agent that competes with PrP for these interactions.

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confidence: 99%

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

Rösener

Gremer

Reinartz

et al. 2018

Journal of Biological Chemistry

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“…Previously, 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 ]. In this study, the potency of the 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.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the outcome of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) cell viability assay with PC-12 cells revealed that all compounds were capable of significantly reversing the cellular toxicity exerted by 1 µM preincubated Aβ(1–42) ( Figure 1 B and [ 7 , 16 ]), without negative impact on cell viability on their own.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we compared in vivo efficiencies of the D3-derivatives RD2, RD2RD2, RD2D3, and D3D3, which were the most efficient compounds in vitro. The direct comparison of the influence of RD2 vs. D3 or D3D3 vs. D3 on Aβ oligomer elimination efficiencies, as measured by the QIAD assay, revealed that all tested peptides significantly reduced the amount of Aβ oligomers; however, RD2 and D3D3 performed significantly better than D3 (RD2 71%, D3D3 96%, and D3 51% oligomer reduction) [ 8 , 16 ]. In vivo in the current study, it was demonstrated that RD2 and D3D3 improved cognitive performances of APP SL mice by oral application of moderate doses over six weeks.…”

Section: Discussionmentioning

confidence: 99%

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Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer’s Disease

et al. 2017

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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.

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“…Hence, it is conceivable that CARPs, such as poly-arginine molecules due to their multivalent arginine arrangement behave in a similar fashion to arginine clusters to prevent protein aggregation. For example, CARPs that inhibit Aβ oligomer formation, which is considered neurotoxic include KLVFFRRRRRR (net charge +7) and R5 (RRRRRR: net charge +5) (351), 15M (Ac-VITNPNRRNRTPQMLKR-NH 2 : net charge +5) (352) SRPGLRR (net charge +3) (353), RR-7-animo-4trifluromethylcoumarin (net charge +3) (354) RI-OR2-TAT (Ac-rGffvlkGrrrrkkrGy-NH 2 : charge +9) (355) R8-Aβ (25-35) (rrrrrrrr-gsnkgaiiglm: net charge +10) (356), and the related D3 and RD2 peptides ( Table 1) (28,29). In a mouse model of Alzheimer's disease, R9 administered subcutaneously over 4 weeks, decreased brain Aβ deposits by 15%, albeit the reduction was not statistically significant (357).…”

Section: Inhibiting Protein Aggregation In Neurodegenerative Disordersmentioning

confidence: 99%

Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action

2020

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There are virtually no clinically available neuroprotective drugs for the treatment of acute and chronic neurological disorders, hence there is an urgent need for the development of new neuroprotective molecules. Cationic arginine-rich peptides (CARPs) are an expanding and relatively novel class of compounds, which possess intrinsic neuroprotective properties. Intriguingly, CARPs possess a combination of biological properties unprecedented for a neuroprotective agent including the ability to traverse cell membranes and enter the CNS, antagonize calcium influx, target mitochondria, stabilize proteins, inhibit proteolytic enzymes, induce pro-survival signaling, scavenge toxic molecules, and reduce oxidative stress as well as, having a range of anti-inflammatory, analgesic, anti-microbial, and anti-cancer actions. CARPs have also been used as carrier molecules for the delivery of other putative neuroprotective agents across the blood-brain barrier and blood-spinal cord barrier. However, there is increasing evidence that the neuroprotective efficacy of many, if not all these other agents delivered using a cationic arginine-rich cell-penetrating peptide (CCPPs) carrier (e.g., TAT) may actually be mediated largely by the properties of the carrier molecule, with overall efficacy further enhanced according to the amino acid composition of the cargo peptide, in particular its arginine content. Therefore, in reviewing the neuroprotective mechanisms of action of CARPs we also consider studies using CCPPs fused to a putative neuroprotective peptide. We review the history of CARPs in neuroprotection and discuss in detail the intrinsic biological properties that may contribute to their cytoprotective effects and their usefulness as a broad-acting class of neuroprotective drugs.

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The Aβ oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology

Cited by 43 publications

References 40 publications

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer’s Disease

Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action

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