The amyloid precursor protein (APP) is a type I transmembrane protein with unknown physiological function. Amyloidogenic processing of APP causes the generation of different cleavage products amongst b-amyloid and the APP C-terminal (APP-CT) fragment.
1D, cerebral organoid 3D cell culture and human hippocampal post-mortem tissue were used to study APP-CT signalling in combination with immunofluorescence, -precipitation, confocal and STED imaging.
The current study demonstrates that APP-CT signals to the nucleus causing the generation of dynamic aggregates consisting of FE65 and the tumour suppressors p53 and PML. PML aggregates fuse over time depending on the APP nuclear signalling and complexes of the APP-CT/p53/PML and FE65 are present in the aged human post-mortem brain but not in cerebral organoids. Precise quantification revealed that AD brains show a significant loss of these nuclear aggregates in areas with high plaque load. The PML aggregates are co-localized to the herpes simplex virus in the human brain.
Our data show that APP-CT signalling recruits the nuclear PML body machinery and is of central relevance for neurodegeneration in AD with a potential function in viral defence.