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Do We Need Anti-Prion Compounds to Treat Alzheimer’s Disease?

Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany
Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
Author to whom correspondence should be addressed.
Academic Editor: Gal Bitan
Molecules 2019, 24(12), 2237;
Received: 21 May 2019 / Revised: 6 June 2019 / Accepted: 13 June 2019 / Published: 15 June 2019
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
Background: While phase III clinical trials for the treatment of Alzheimer’s disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) behave like prions. Irrespective of the question of whether AD is theoretically or practically contagious, the presence of a self-replicating toxic etiologic agent in the brains of AD patients must have decisive consequences for drug development programs and clinical trial designs. Objectives: We intend to challenge the hypothesis that the underlying etiologic agent of AD is behaving prion-like. We want to discuss whether the outcome of clinical trials could have been predicted based on this hypothesis, and whether compounds that directly disassemble the toxic prion could be more beneficial for AD treatment. Method: We collected publicly accessible pre-clinical efficacy data of Aβ targeting compounds that failed or still are in phase III clinical trials. We describe the desired properties of an anti-prion compound and compare it the properties of past and current phase III drug candidates. Results: We could not find convincing and reproducible pre-clinical efficacy data of past and current phase III drug candidates on cognition other than in preventive treatment settings. The desired properties of an anti-Aβ-prionic compound are fulfilled by the drug candidate RD2, which has been developed to directly disassemble toxic Aβ oligomers. Conclusion: RD2 is the first anti-prion drug candidate. It is able to enhance cognition and impede neurodegeneration in three different transgenic AD mouse models, even under truly non-preventive conditions and even when applied orally. In addition, it is safe in humans. View Full-Text
Keywords: Alzheimer’s disease; amyloid β; Aβ oligomers; anti-prion; oral treatment; d-enantiomeric peptides Alzheimer’s disease; amyloid β; Aβ oligomers; anti-prion; oral treatment; d-enantiomeric peptides
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MDPI and ACS Style

Willbold, D.; Kutzsche, J. Do We Need Anti-Prion Compounds to Treat Alzheimer’s Disease? Molecules 2019, 24, 2237.

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