TY - JOUR TI - Amyloid precursor protein elevates fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load AU - Marks, David AU - Heinen, Natalie AU - Bachmann, Lisa AU - Meermeyer, Sophia AU - Werner, Michelle AU - Gallego, Lucia AU - Hemmerich, Peter AU - Bader, Verian AU - Winklhofer, Konstanze F. AU - Schröder, Elisabeth AU - Knauer, Shirley K. AU - Müller, Thorsten T2 - Acta Neuropathologica Communications AB - 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. DA - 2021/04/13/ PY - 2021 DO - 10.1186/s40478-021-01174-x DP - BioMed Central VL - 9 IS - 1 SP - 66 J2 - Acta Neuropathologica Communications SN - 2051-5960 UR - https://doi.org/10.1186/s40478-021-01174-x Y2 - 2021/04/15/22:28:29 KW - 3D culture KW - APP-CT50 KW - Alzheimer’s disease KW - Amyloidogenic plaques KW - HSV KW - Human brain KW - IPSC-derived cerebral organoids KW - Nuclear complexes KW - PML KW - Viral defence ER -