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

AbstractThe 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.

Download Full-text

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

10.1101/2020.04.16.001255 ◽

2020 ◽

Author(s):

David Marks ◽

Natalie Heinen ◽

Lisa Bachmann ◽

Sophia Meermeyer ◽

Michelle Werner ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Human Brain ◽

Current Knowledge ◽

Transmembrane Protein ◽

Significant Loss ◽

Nuclear Bodies ◽

Precursor Protein ◽

Type I ◽

Plaque Load ◽

Defence Strategy

AbstractThe 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 comprising its adapter protein FE65 and the tumour suppressor proteins p53 and PML. The PML nuclear body generation, known to be of relevance in virus defence and cell division, is induced and fusion occurs over time depending on APP signalling. We further show that the nuclear aggregates of APP C-terminal (APP-CT) 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 loss 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-CT signalling to the nucleus takes place in the aged human brain and is potentially involved in the pathophysiology of AD. Taken the current knowledge on PML bodies into account, we hypothesize a new role for APP as a twofold virus response protein. The APP-dependent defence strategy includes Aß-virus interaction at the extracellular matrix and APP-CT driven PML aggregation in the nucleus to encapsulate the viral nucleic acid. This defence strategy preferentially occurs in high-plaque regions of the human brain and overstimulation of this pathway results in a pyrrhic victory.

Download Full-text

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

10.21203/rs.3.rs-74943/v1 ◽

2020 ◽

Author(s):

David Marks ◽

Natalie Heinen ◽

Lisa Bachmann ◽

Sophia Meermeyer ◽

Michelle Werner ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Transmembrane Protein ◽

3D Cell Culture ◽

Significant Loss ◽

Nuclear Bodies ◽

Precursor Protein ◽

Type I ◽

Post Mortem ◽

Plaque Load ◽

Simplex Virus

Abstract BackgroundThe 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.METHODS1D, 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.RESULTSThe 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.CONCLUSIONSOur 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.

Download Full-text

The structural biology of the amyloid precursor protein APP – a complex puzzle reveals its multi-domain architecture

Biological Chemistry ◽

10.1515/hsz-2013-0280 ◽

2014 ◽

Vol 395 (5) ◽

pp. 485-498 ◽

Cited By ~ 17

Author(s):

Ina Coburger ◽

Sandra Hoefgen ◽

Manuel E. Than

Keyword(s):

Amyloid Precursor Protein ◽

Neuronal Development ◽

Transmembrane Protein ◽

Transmembrane Helix ◽

Domain Architecture ◽

Three Dimensional ◽

Proteolytic Processing ◽

Precursor Protein ◽

Type I ◽

Independent Functions

Abstract The amyloid precursor protein (APP) and its processing are widely believed to be central for the etiology of Alzheimer’s disease (AD) and appear essential for neuronal development and cell homeostasis in mammals. Many studies show the proteolysis of APP by the proteases α-, β- and γ-secretase, functional aspects of the protein and the structure of individual domains. It is, however, largely unclear and currently also widely debated of how the structures of individual domains and their interactions determine the observed functionalities of APP and how they are arranged within the three-dimensional architecture of the entire protein. Further unanswered questions relate to the physiologic function of APP, the regulation of its proteolytic processing and the structural and functional effect of its cellular trafficking and processing. In this review, we summarize our current understanding of the structure-function-relationship of the multi-domain protein APP. This type-I transmembrane protein consists of the two folded E1 and E2 segments that are connected to one another and to the single transmembrane helix by flexible segments and likely fulfills several independent functions.

Download Full-text

Alzheimer beta/A4 amyloid precursor protein in human brain: aging-associated increases in holoprotein and in a proteolytic fragment.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.88.20.8910 ◽

1991 ◽

Vol 88 (20) ◽

pp. 8910-8914 ◽

Cited By ~ 67

Author(s):

C. Nordstedt ◽

S. E. Gandy ◽

I. Alafuzoff ◽

G. L. Caporaso ◽

K. Iverfeldt ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Human Brain ◽

Brain Aging ◽

Precursor Protein ◽

Proteolytic Fragment

Download Full-text

Isolating Components of Human Brain: The Purification of Aβ and the Alzheimer’s Amyloid Precursor Protein

Using CNS Autopsy Tissue in Psychiatric Research: A Practical Guide ◽

10.4324/9781482283419-10 ◽

2019 ◽

pp. 151-168

Keyword(s):

Amyloid Precursor Protein ◽

Human Brain ◽

Precursor Protein

Download Full-text

Rhesus Macaque Rhadinovirus Encodes a Viral Interferon Regulatory Factor To Disrupt Promyelocytic Leukemia Nuclear Bodies and Antagonize Type I Interferon Signaling

Journal of Virology ◽

10.1128/jvi.02147-18 ◽

2019 ◽

Vol 93 (6) ◽

Cited By ~ 1

Author(s):

Laura K. Springgay ◽

Kristin Fitzpatrick ◽

Byung Park ◽

Ryan D. Estep ◽

Scott W. Wong

Keyword(s):

Immune Response ◽

Rhesus Macaque ◽

Promyelocytic Leukemia ◽

Nuclear Bodies ◽

Type I ◽

Type I Ifn ◽

Regulatory Factors ◽

Successful Infection ◽

Promyelocytic Leukemia Nuclear Bodies

ABSTRACTInterferon (IFN) production and the subsequent induction of IFN-stimulated genes (ISGs) are highly effective innate strategies utilized by cells to protect against invading pathogens, including viruses. Critical components involved in this innate process are promyelocytic leukemia nuclear bodies (PML-NBs), which are subnuclear structures required for the development of a robust IFN response. As such, PML-NBs serve as an important hurdle for viruses to overcome to successfully establish an infection. Both Kaposi’s sarcoma-associated herpesvirus (KSHV) and the closely related rhesus macaque rhadinovirus (RRV) are unique for encoding viral homologs of IFN regulatory factors (termed vIRFs) that can manipulate the host immune response by multiple mechanisms. All four KSHV vIRFs inhibit the induction of IFN, while vIRF1 and vIRF2 can inhibit ISG induction downstream of the IFN receptor. Less is known about the RRV vIRFs. RRV vIRF R6 can inhibit the induction of IFN by IRF3; however, it is not known whether any RRV vIRFs inhibit ISG induction following IFN receptor signaling. In our present study, we demonstrate that the RRV vIRF R12 aids viral replication in the presence of the type I IFN response. This is achieved in part through the disruption of PML-NBs and the inhibition of robust ISG transcription.IMPORTANCEKSHV and RRV encode a unique set of homologs of cellular IFN regulatory factors, termed vIRFs, which are hypothesized to help these viruses evade the innate immune response and establish infections in their respective hosts. Our work elucidates the role of one RRV vIRF, R12, and demonstrates that RRV can dampen the type I IFN response downstream of IFN signaling, which would be important for establishing a successful infectionin vivo.

Download Full-text