{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T19:04:58Z","timestamp":1789844698573,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,6,15]],"date-time":"2019-06-15T00:00:00Z","timestamp":1560556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["18PTC-19-605853"],"award-info":[{"award-number":["18PTC-19-605853"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Helmholtzgemeinschaft","award":["Portfolio Drug Research"],"award-info":[{"award-number":["Portfolio Drug Research"]}]},{"DOI":"10.13039\/501100001656","name":"Helmholtz-Gemeinschaft","doi-asserted-by":"publisher","award":["Portfolio Technology and Medicine"],"award-info":[{"award-number":["Portfolio Technology and Medicine"]}],"id":[{"id":"10.13039\/501100001656","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: While phase III clinical trials for the treatment of Alzheimer\u2019s disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (A\u03b2) 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 A\u03b2 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-A\u03b2-prionic compound are fulfilled by the drug candidate RD2, which has been developed to directly disassemble toxic A\u03b2 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.<\/jats:p>","DOI":"10.3390\/molecules24122237","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T03:24:41Z","timestamp":1560741881000},"page":"2237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Do We Need Anti-Prion Compounds to Treat Alzheimer\u2019s Disease?"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0065-7366","authenticated-orcid":false,"given":"Dieter","family":"Willbold","sequence":"first","affiliation":[{"name":"Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum J\u00fclich, 52425 J\u00fclich, Germany"},{"name":"Institut f\u00fcr Physikalische Biologie, Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Kutzsche","sequence":"additional","affiliation":[{"name":"Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum J\u00fclich, 52425 J\u00fclich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10626","DOI":"10.1021\/bi00158a027","article-title":"Structure and novel exons of the human. tau. gene","volume":"31","author":"Andreadis","year":"1992","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0166-2236(91)90105-4","article-title":"Molecular characterization of microtubule-associated proteins tau and MAP2","volume":"14","author":"Goedert","year":"1991","journal-title":"Trends Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1002\/mds.20539","article-title":"Tau gene mutations and their effects","volume":"20","author":"Goedert","year":"2005","journal-title":"Mov. 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