Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein

2005 ◽  
Vol 33 (2) ◽  
pp. 335-338 ◽  
Author(s):  
N.M. Hooper
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Prion Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Copper Binding ◽  
Secretase Activity ◽  
Aβ Amyloid ◽  
A Disintegrin And Metalloproteinase

In the amyloidogenic pathway, the APP (amyloid precursor protein) is proteolytically processed by the β- and γ-secretases to release the Aβ (amyloid-β) peptide that is neurotoxic and aggregates in the brains of patients suffering from Alzheimer's disease. In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain, precluding deposition of intact Aβ peptide. The cellular form of the PrPC (prion protein) undergoes reactive oxygen species-mediated β-cleavage within the copper-binding octapeptide repeats or, alternatively, α-cleavage within the central hydrophobic neurotoxic domain. In addition, PrPC is shed from the membrane by the action of a zinc metalloprotease. Members of the ADAM (a disintegrin and metalloproteinase) family of zinc metalloproteases, notably ADAM10 and TACE (ADAM17) display α-secretase activity towards APP and appear to be responsible for the α-cleavage of PrPC. The amyloidogenic cleavage of APP by the β- and γ-secretases appears to occur preferentially in cholesterol-rich lipid rafts, while the conversion of PrPC into the infectious form PrPSc also appears to occur in these membrane domains.

Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease

2007 ◽  
Vol 35 (5) ◽  
pp. 974-979 ◽  
Author(s):  
R.B. Parsons ◽  
B.M. Austen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Protein Interactions ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

Novel heparan sulphate analogues: inhibition of β-secretase cleavage of amyloid precursor protein

2005 ◽  
Vol 33 (5) ◽  
pp. 1116-1118 ◽  
Author(s):  
S.J. Patey ◽  
E.A. Yates ◽  
J.E. Turnbull
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulphate ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Neuritic Plaques ◽  
Rate Limiting Step ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The role of HS (heparan sulphate) in the pathology of AD (Alzheimer's disease) is multifaceted. HS and other glycosaminoglycans have been widely reported to be associated with neuritic plaques. HS has also been shown to promote the aggregation of Aβ (amyloid β-peptide), the proteinaceous component of neuritic plaques. Recently, we described a novel and contrasting role for HS in the pathology of AD: HS can inhibit the formation of Aβ, by directly interacting with the protease BACE1 (β-site amyloid precursor protein cleaving enzyme 1; β-secretase 1), that cleaves the amyloid precursor protein and is the rate limiting step in the generation of Aβ. Here, we review the current roles of HS and the potential for HS-derivatives in the treatment of AD.

scholarly journals Amyloid-β Peptide Exacerbates the Memory Deficit Caused by Amyloid Precursor Protein Loss-of-Function in Drosophila

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0135741 ◽  
Author(s):  
Isabelle Bourdet ◽  
Aurélie Lampin-Saint-Amaux ◽  
Thomas Preat ◽  
Valérie Goguel
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Memory Deficit ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Loss Of Function ◽  
Protein Loss

scholarly journals Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production

2017 ◽  
Vol 292 (9) ◽  
pp. 3751-3767 ◽  
Author(s):  
Hermeto Gerber ◽  
Fang Wu ◽  
Mitko Dimitrov ◽  
Guillermo M. Garcia Osuna ◽  
Patrick C. Fraering
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide

scholarly journals Inhibition of Glycosphingolipid Biosynthesis Reduces Secretion of the β-Amyloid Precursor Protein and Amyloid β-Peptide

2005 ◽  
Vol 280 (30) ◽  
pp. 28110-28117 ◽  
Author(s):  
Irfan Y. Tamboli ◽  
Kai Prager ◽  
Esther Barth ◽  
Michael Heneka ◽  
Konrad Sandhoff ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Β Amyloid ◽  
Glycosphingolipid Biosynthesis

scholarly journals COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

2013 ◽  
Vol 288 (37) ◽  
pp. 26668-26677 ◽  
Author(s):  
Hongjie Wang ◽  
Debleena Dey ◽  
Ivan Carrera ◽  
Dmitriy Minond ◽  
Elisabetta Bianchi ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Protein Levels

The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice

2006 ◽  
Vol 96 (2) ◽  
pp. 533-540 ◽  
Author(s):  
Masashi Asai ◽  
Chinatsu Hattori ◽  
Nobuhisa Iwata ◽  
Takaomi C. Saido ◽  
Noboru Sasagawa ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
The Novel ◽  
Wild Type ◽  
Secretase Inhibitor

scholarly journals Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription

2004 ◽  
Vol 383 (2) ◽  
pp. 393-399 ◽  
Author(s):  
Fabian DOCAGNE ◽  
Cecilia GABRIEL ◽  
Nathalie LEBEURRIER ◽  
Sylvain LESNÉ ◽  
Yannick HOMMET ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Transforming Growth Factor Β ◽  
Precursor Protein ◽  
Transcriptional Level ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

Abnormal deposition of Aβ (amyloid-β peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-β precursor protein). We have demonstrated previously that TGF-β (transforming growth factor-β), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Aβ. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-β-dependent transcriptional activity. We report the following findings: first, TGF-β is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APPTRE (APP TGF-β-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APPTRE. We also observed that the APPTRE sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-β-dependent activation of APP. TGF-β signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-β-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-β in the regulation of Aβ production.

scholarly journals A cellular model of amyloid precursor protein processing and amyloid-β peptide production

2014 ◽  
Vol 223 ◽  
pp. 114-122 ◽  
Author(s):  
MiMi P. Macias ◽  
Amanda M. Gonzales ◽  
Ashley L. Siniard ◽  
Aaron W. Walker ◽  
Jason J. Corneveaux ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide ◽  
Cellular Model
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