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

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.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01174-x ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

David Marks ◽

Natalie Heinen ◽

Lisa Bachmann ◽

Sophia Meermeyer ◽

Michelle Werner ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Human Brain ◽

Transmembrane Protein ◽

Nuclear Body ◽

Nuclear Bodies ◽

Precursor Protein ◽

Type I ◽

Adapter Protein ◽

Plaque Load ◽

Promyelocytic Leukemia Nuclear Bodies

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.

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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.

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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.

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Side-Chain to Main-Chain Hydrogen Bonding Controls the Intrinsic Backbone Dynamics of the Amyloid Precursor Protein Transmembrane Helix

Biophysical Journal ◽

10.1016/j.bpj.2014.02.013 ◽

2014 ◽

Vol 106 (6) ◽

pp. 1318-1326 ◽

Cited By ~ 29

Author(s):

Christina Scharnagl ◽

Oxana Pester ◽

Philipp Hornburg ◽

Daniel Hornburg ◽

Alexander Götz ◽

...

Keyword(s):

Hydrogen Bonding ◽

Amyloid Precursor Protein ◽

Main Chain ◽

Transmembrane Helix ◽

Precursor Protein ◽

Backbone Dynamics ◽

Side Chain

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Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy

PLoS ONE ◽

10.1371/journal.pone.0136313 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0136313 ◽

Cited By ~ 15

Author(s):

Viviana A. Cavieres ◽

Alexis González ◽

Vanessa C. Muñoz ◽

Claudia P. Yefi ◽

Hianara A. Bustamante ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Proteolytic Processing ◽

Precursor Protein

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Proteolytic processing and cell biological functions of the amyloid precursor protein

Journal of Cell Science ◽

10.1242/jcs.113.11.1857 ◽

2000 ◽

Vol 113 (11) ◽

pp. 1857-1870 ◽

Cited By ~ 12

Author(s):

B. De Strooper ◽

W. Annaert

Keyword(s):

Amyloid Precursor Protein ◽

Stress Responses ◽

Neuronal Cell ◽

Principal Component ◽

Proteolytic Processing ◽

Cholesterol Homeostasis ◽

Precursor Protein ◽

Axonal Elongation ◽

Beta Peptide ◽

Complex Protein

Recent research has identified some key players involved in the proteolytic processing of amyloid precursor protein (APP) to amyloid beta-peptide, the principal component of the amyloid plaques in Alzheimer patients. Interesting parallels exists with the proteolysis of other proteins involved in cell differentiation, cholesterol homeostasis and stress responses. Since the cytoplasmic domain of APP is anchored to a complex protein network that might function in axonal elongation, dendritic arborisation and neuronal cell migration, the proteolysis of APP might be critically involved in intracellular signalling events.

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Amyloid Precursor Protein (APP) and GABAergic Neurotransmission

Cells ◽

10.3390/cells8060550 ◽

2019 ◽

Vol 8 (6) ◽

pp. 550 ◽

Cited By ~ 9

Author(s):

Bor Luen Tang

Keyword(s):

Amyloid Precursor Protein ◽

Gabab Receptor ◽

Reversal Potential ◽

Proteolytic Processing ◽

Precursor Protein ◽

Mammalian Brain ◽

Gabaergic Neurotransmission ◽

Physiological Importance ◽

Presynaptic Plasma Membrane ◽

Etiological Agents

The amyloid precursor protein (APP) is the parent polypeptide from which amyloid-beta (Aβ) peptides, key etiological agents of Alzheimer’s disease (AD), are generated by sequential proteolytic processing involving β- and γ-secretases. APP mutations underlie familial, early-onset AD, and the involvement of APP in AD pathology has been extensively studied. However, APP has important physiological roles in the mammalian brain, particularly its modulation of synaptic functions and neuronal survival. Recent works have now shown that APP could directly modulate γ-aminobutyric acid (GABA) neurotransmission in two broad ways. Firstly, APP is shown to interact with and modulate the levels and activity of the neuron-specific Potassium-Chloride (K+-Cl−) cotransporter KCC2/SLC12A5. The latter is key to the maintenance of neuronal chloride (Cl−) levels and the GABA reversal potential (EGABA), and is therefore important for postsynaptic GABAergic inhibition through the ionotropic GABAA receptors. Secondly, APP binds to the sushi domain of metabotropic GABAB receptor 1a (GABABR1a). In this regard, APP complexes and is co-transported with GABAB receptor dimers bearing GABABR1a to the axonal presynaptic plasma membrane. On the other hand, secreted (s)APP generated by secretase cleavages could act as a GABABR1a-binding ligand that modulates presynaptic vesicle release. The discovery of these novel roles and activities of APP in GABAergic neurotransmission underlies the physiological importance of APP in postnatal brain function.

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Adaptor protein 2–mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing

Molecular Biology of the Cell ◽

10.1091/mbc.e11-11-0944 ◽

2012 ◽

Vol 23 (12) ◽

pp. 2339-2351 ◽

Cited By ~ 46

Author(s):

Yogikala Prabhu ◽

Patricia V. Burgos ◽

Christina Schindler ◽

Ginny G. Farías ◽

Javier G. Magadán ◽

...

Keyword(s):

Plasma Membrane ◽

Amyloid Precursor Protein ◽

Secretory Pathway ◽

Brefeldin A ◽

Adaptor Protein ◽

Proteolytic Processing ◽

Precursor Protein ◽

Amyloid Precursor Protein Processing ◽

Intermediate Compartment ◽

Golgi Network

The β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.

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