Amyloid precursor protein elevates fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load

David Marks,Peter Hemmerich,Natalie Heinen,Verian Bader,Sophia Meermeyer,Lucia Gallego,Michelle Werner,Thorsten Müller,Elisabeth Schröder,Konstanze F Winklhofer,Lisa Bachmann,Shirley K Knauer

doi:10.1186/s40478-021-01174-x

Abstract

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.

Highlights

Increased amyloidogenic processing of the amyloid precursor protein (APP) occurs in sporadic Alzheimer’s disease (AD) [1], in familial AD with mutations in APP or in its processing enzymes [2], and in trisomy 21 patients [3]
In order to not overwhelm the cell with unnecessary expression constructs, we passed on APP-CT50 expression for some of the subsequent experiments
APP-CT50 signal transduction is of high relevance for AD and causes a reduction in the number of Promyelocytic leukemia protein (PML) bodies in nuclei close to AD relevant hot spots

Summary

Introduction

Increased amyloidogenic processing of the amyloid precursor protein (APP) occurs in sporadic Alzheimer’s disease (AD) [1], in familial AD with mutations in APP or in its processing enzymes [2], and in trisomy 21 patients [3]. The presence of the histone acetyl transferase (TIP60) and the DNA helicase (BLM) in the complex points to a functional role in essential biological mechanisms such as gene expression, DNA replication/damage/repair or chromatin modification. PML-NBs are highly dynamic structures with respect to mobility, composition, architecture, and function [15]. While their precise biochemical functions have not been elucidated yet, they have been linked to many aspects of chromatin biology, including transcription, histone modification, repair and recombination, degradation, genome maintenance [16]. We demonstrate that PML nuclear bodies interact with highly mobile APP-CT complexes and progressively form immobile large nuclear structures with relevance for AD pathophysiology

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