Zusammenfassung
Zahlreiche auf der Amyloid-Hypothese basierende klinische Studien sind gescheitert. Heißt dies nun, dass die Mechanismen der Alzheimer-Erkrankung neu überdacht werden müssen und dass Amyloid nicht der Auslöser der Erkrankung ist? Gegen diese fatalistische Ansicht spricht die Genetik der familiären Alzheimer-Erkrankung. Mutationen in allen assoziierten Genen beeinflussen ohne Ausnahme die Amyloidaggregation und eine protektive Mutation reduziert die Amyloidbildung. Klinische Studien scheitern, weil Sekretaseinhibitoren die Prozessierung zahlreicher physiologisch wichtiger Substrate der Sekretasen verhindern und die Erkrankung lange vor den ersten Symptomen angelegt wird. Am Beispiel anderer prototypischer Amyloidosen wird eine erfolgreiche Behandlung mit Amyloidmedikamenten beschrieben und neue mikrogliale Zielmoleküle werden diskutiert.
Abstract
Numerous amyloid-based clinical studies have recently failed. Does this mean that the mechanisms of Alzheimer’s disease have to be reinvestigated and that amyloid is not the trigger of the disease? Strong genetic evidence from familial Alzheimer’s disease contradicts this fatalistic opinion. Mutations in all genes associated with familial Alzheimer’s disease affect amyloid metabolism and aggregation. Moreover, a protective mutation reduces amyloid production by 20–30% throughout the lifetime. Clinical studies rather failed because secretase inhibitors block cleavage of numerous other physiologically important substrates of secretases. Moreover, the disease is initiated decades before symptoms occur. Successful treatment attempts with anti-amyloid medication based on other prototype amyloidoses are described. Finally, new therapeutic target molecules expressed in microglia cells are discussed.
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C. Haass kooperiert mit DENALI, hat 2018 an einem Advisory Board Meeting von Biogen teilgenommen, ist Berater bei ISAR-Bioscience und hat ein Sprecherhonorar von Novartis und Roche erhalten. J. Levin gibt an, keinen Interessenkonflikt zu haben.
Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.
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Haass, C., Levin, J. Hat die Alzheimer-Forschung versagt?. Nervenarzt 90, 884–890 (2019). https://doi.org/10.1007/s00115-019-0751-1
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DOI: https://doi.org/10.1007/s00115-019-0751-1