scholarly journals Proteolytic Processing of Amyloid-β Precursor Protein by Secretases Does Not Require Cell Surface Transport

2004 ◽  
Vol 279 (45) ◽  
pp. 47101-47108 ◽  
Author(s):  
Mikhail Khvotchev ◽  
Thomas C. Südhof
Keyword(s):  
Cell Surface ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Surface Transport

Deposition of amyloid fibrils promotes cell-surface accumulation of amyloid β precursor protein

2004 ◽  
Vol 16 (3) ◽  
pp. 617-629 ◽  
Author(s):  
Lorena Heredia ◽  
Rong Lin ◽  
Francisco Solá Vigo ◽  
Gabriela Kedikian ◽  
Jorge Busciglio ◽  
...  
Keyword(s):  
Cell Surface ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Precursor Protein

scholarly journals Cell surface expression of membrane-anchored v-sis gene products: glycosylation is not required for cell surface transport.

1986 ◽  
Vol 103 (6) ◽  
pp. 2311-2322 ◽  
Author(s):  
M Hannink ◽  
D J Donoghue
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Gene Product ◽  
Surface Expression ◽  
Proteolytic Processing ◽  
Biologically Active ◽  
Platelet Derived Growth Factor ◽  
Cell Surface Expression ◽  
Gene Products ◽  
Surface Transport

The v-sis gene is able to transform cells by production of a growth factor that is structurally related to platelet-derived growth factor. This growth factor has been detected in the conditioned media of v-sis transformed cells, and is able to stimulate the autophosphorylation of the platelet-derived growth factor receptor. We have used the v-sis gene product to analyze the role of protein-encoded signals in cell surface transport. We constructed several gene fusions that encode transmembrane forms of the v-sis gene product. These membrane-anchored forms of the v-sis gene product are properly folded into a native structure, as indicated by their dimerization, glycosylation, and NH2-terminal proteolytic processing. Indirect immunofluorescence demonstrated that several of these membrane-anchored gene products are transported to the cell surface. Removal of the N-linked glycosylation site from the v-sis gene product did not prevent cell surface transport. Several of these mutant genes are able to induce focus formation in NIH3T3 cells, providing further evidence that the membrane-anchored proteins are properly folded. These results demonstrate that N-linked glycosylation is not required for the cell surface transport of a protein that is in a native, biologically active conformation. These results provide a correlation between cell surface expression of the membrane-anchored v-sis gene products and transformation.

scholarly journals The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
David A. Hicks ◽  
Alys C. Jones ◽  
Stuart M. Pickering-Brown ◽  
Nigel M. Hooper
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Aβ Peptides ◽  
App Processing ◽  
Cellular Expression ◽  
Aβ Generation ◽  
Human Neuronal Cells ◽  
Inducible Cell Line

Abstract Alzheimer’s disease (AD) is a neurodegenerative condition, of which one of the cardinal pathological hallmarks is the extracellular accumulation of amyloid β (Aβ) peptides. These peptides are generated via proteolysis of the amyloid precursor protein (APP), in a manner dependent on the β-secretase, BACE1 and the multicomponent γ-secretase complex. Recent data also suggest a contributory role in AD of transactive response DNA binding protein 43 (TDP-43). There is little insight into a possible mechanism linking TDP-43 and APP processing. To this end, we used cultured human neuronal cells to investigate the ability of TDP-43 to interact with APP and modulate its proteolytic processing. Immunocytochemistry showed TDP-43 to be spatially segregated from both the extranuclear APP holoprotein and its nuclear C-terminal fragment. The latter (APP intracellular domain) was shown to predominantly localise to nucleoli, from which TDP-43 was excluded. Furthermore, neither overexpression of each of the APP isoforms nor siRNA-mediated knockdown of APP had any effect on TDP-43 expression. Doxycycline-stimulated overexpression of TDP-43 was explored in an inducible cell line. Overexpression of TDP-43 had no effect on expression of the APP holoprotein, nor any of the key proteins involved in its proteolysis. Furthermore, increased TDP-43 expression had no effect on BACE1 enzymatic activity or immunoreactivity of Aβ1-40, Aβ1-42 or the Aβ1-40:Aβ1-42 ratio. Also, siRNA-mediated knockdown of TDP-43 had no effect on BACE1 immunoreactivity. Taken together, these data indicate that TDP-43 function and/or dysfunction in AD is likely independent from dysregulation of APP expression and proteolytic processing and Aβ generation.

scholarly journals Effects of the amyloid precursor protein Glu693→Gln ‘Dutch’ mutation on the production and stability of amyloid β-protein

1999 ◽  
Vol 340 (3) ◽  
pp. 703-709 ◽  
Author(s):  
Deborah J. WATSON ◽  
Dennis J. SELKOE ◽  
David B. TEPLOW
Keyword(s):  
Amyloid Precursor Protein ◽  
Disease Process ◽  
Amyloid Β ◽  
Cerebral Haemorrhage ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Amyloid Β Protein ◽  
Aβ Peptides ◽  
Β Protein ◽  
Dutch Mutation

Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), is a cerebral amyloidosis characterized by prominent vascular deposits and fatal haemorrhages. The disorder is caused by a point mutation in codon 693 of the gene encoding the amyloid precursor protein (APP), resulting in a Glu → Gln amino acid substitution at position 22 of the amyloid β-protein (Aβ) region. The pathogenetic mechanisms of HCHWA-D are unknown but could involve alterations in the proteolytic processing of APP and in amyloid fibril formation. We examined Aβ production and stability by using cultured human embryonic kidney 293 cells stably expressing wild-type or ‘Dutch’ APP. Radiosequencing and quantitative immunoprecipitation experiments showed that cells expressing Dutch APP secreted increased quantities of Aβ peptides beginning at Asp1, and of truncated peptides beginning at Val18 and Phe19. The ratio of levels of 4 kDa (Aβ) to 3 kDa (p3) peptides remained constant due to co-ordinate decreases in other peptide species. Novel truncated or elongated peptides were not observed. Pulse-chase experiments showed that the Dutch mutation did not affect the stability of the Aβ or p3 populations. These results are consistent with a disease process in which the Dutch mutation results in the production of Aβ peptides with enhanced propensities for fibrillogenesis, leading to accelerated vascular deposition and disease.

scholarly journals The cerebrospinal-fluid soluble form of Alzheimer's amyloid β is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex

1993 ◽  
Vol 293 (1) ◽  
pp. 27-30 ◽  
Author(s):  
J Ghiso ◽  
E Matsubara ◽  
A Koudinov ◽  
N H Choi-Miura ◽  
M Tomita ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Amyloid Fibrils ◽  
Membrane Attack Complex ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Neuritic Plaque ◽  
Soluble Form ◽  
Direct Binding

The amyloid fibrils deposited in Alzheimer's neuritic plaque cores and cerebral blood vessels are mainly composed of aggregated forms of a unique peptide, 39-42 amino acids long, named amyloid beta (A beta). A similar, although soluble, A beta (‘sA beta’) has been identified in cerebrospinal fluid, plasma and cell supernatants, indicating that it is normally produced by proteolytic processing of its precursor protein, amyloid precursor protein (APP). Using direct binding experiments we have isolated and characterized an 80 kDa circulating protein that specifically interacts with a synthetic peptide identical with A beta. The protein was unmistakably identified as SP-40,40 or ApoJ, a cytolytic inhibitor and lipid carrier, by means of amino acid sequence and immunoreactivity with specific antibodies. Immunoprecipitation with anti-SP-40,40 retrieved soluble A beta from cerebrospinal fluid, indicating that the interaction occurs in vivo.

scholarly journals The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2

2016 ◽  
Vol 397 (8) ◽  
pp. 777-790 ◽  
Author(s):  
Anna-Madeleine Beckmann ◽  
Konstantin Glebov ◽  
Jochen Walter ◽  
Olaf Merkel ◽  
Martin Mangold ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Iron Homeostasis ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
App Processing ◽  
Kunitz Domain ◽  
Membrane Bound ◽  
Aβ Generation ◽  
Slow Binding Inhibitor

Abstract Proteolytic processing of the amyloid precursor protein (APP) leads to amyloid-β (Aβ) peptides. So far, the mechanism of APP processing is insufficiently characterized at the molecular level. Whereas the knowledge of Aβ generation by several proteases has been expanded, the contribution of the Kunitz-type protease inhibitor domain (KPI) present in two major APP isoforms to the complex proteolytic processing of APP is poorly understood. In this study, we have identified KPI-containing APP as a very potent, slow-binding inhibitor for the membrane-bound proteolytic regulator of iron homeostasis matriptase-2 by forming stable complexes with its target protease in HEK cells. Inhibition and complex formation depend on the intact KPI domain. By inhibiting matriptase-2, KPI-containing APP is protected from matriptase-2-mediated proteolysis within the Aβ region, thus preventing the generation of N-terminally truncated Aβ.

scholarly journals BECN1/Beclin 1 sorts cell-surface APP/amyloid β precursor protein for lysosomal degradation

Autophagy ◽  
2016 ◽  
Vol 12 (12) ◽  
pp. 2404-2419 ◽  
Author(s):  
Gayathri Swaminathan ◽  
Wan Zhu ◽  
Edward D. Plowey
Keyword(s):  
Cell Surface ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Beclin 1 ◽  
Lysosomal Degradation
Sign in / Sign up

Export Citation Format

Share Document