David Marks, Natalie Heinen, Lisa Bachmann, Sophia Meermeyer, Michelle Werner, Lucia Gallego Villarejo, Peter Hemmerich, Verian Bader, Konstanze Winklhofer, Elisabeth Schröder, Shirley Knauer, Thorsten Müller
- The amyloid precursor protein (APP) is a type I transmembrane protein with unknown physiological function but potential impact in neurodegeneration. The current study demonstrates that APP signals to the nucleus causing the generation of aggregates consisting of its adapter protein FE65, the histone acetyltransferase TIP60 and the tumour suppressor proteins p53 and PML. APP C-terminal (APP-CT50) complexes co-localize and co-precipitate with p53 and PML. The PML nuclear body generation is induced and fusion occurs over time depending on APP signalling and STED imaging revealed active gene expression within the complex. We further show that the nuclear aggregates of APP-CT50 fragments together with PML and FE65 are present in the aged human brain but not in cerebral organoids differentiated from iPS cells. Notably, human Alzheimer’s disease brains reveal a highly significant reduction of these nuclear aggregates in areas with high plaque load compared to plaque-free areas of the same individual. Based on these results we conclude that APP-CT50 signalling to the nucleus takes place in the aged human brain and is involved in the pathophysiology of AD.
MetadatenAuthor: | David MarksORCiDGND, Natalie HeinenORCiDGND, Lisa BachmannGND, Sophia MeermeyerGND, Michelle WernerGND, Lucia Gallego VillarejoGND, Peter HemmerichGND, Verian BaderORCiDGND, Konstanze WinklhoferORCiDGND, Elisabeth SchröderGND, Shirley KnauerGND, Thorsten MüllerORCiDGND |
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URN: | urn:nbn:de:hbz:294-97783 |
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DOI: | https://doi.org/10.1186/s40478-021-01174-x |
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Parent Title (English): | Acta Neuropathologica Communications |
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Publisher: | BioMed Central |
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Place of publication: | London |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2023/03/27 |
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Date of first Publication: | 2021/04/13 |
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Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
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Tag: | 3D culture; APP-CT50; Alzheimer’s disease; Amyloidogenic plaques; HSV; Human brain; IPSC-derived cerebral organoids; Nuclear complexes; PML; Viral defence |
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Volume: | 9 |
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Issue: | Article 66 |
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First Page: | 66-1 |
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Last Page: | 66-16 |
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Note: | Dieser Beitrag ist auf Grund des DEAL-Springer-Vertrages frei zugänglich. |
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Dewey Decimal Classification: | Naturwissenschaften und Mathematik / Chemie, Kristallographie, Mineralogie |
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open_access (DINI-Set): | open_access |
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faculties: | Fakultät für Chemie und Biochemie |
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Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |
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