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Ortega2013 - Interplay between secretases determines biphasic amyloid-beta level


ABSTRACT: Ortega2013 - Interplay between secretases determines biphasic amyloid-beta level This model is described in the article: Interplay between ?-, ?-, and ?-secretases determines biphasic amyloid-? protein level in the presence of a ?-secretase inhibitor. Ortega F, Stott J, Visser SA, Bendtsen C. J. Biol. Chem. 2013 Jan; 288(2): 785-792 Abstract: Amyloid-? (A?) is produced by the consecutive cleavage of amyloid precursor protein (APP) first by ?-secretase, generating C99, and then by ?-secretase. APP is also cleaved by ?-secretase. It is hypothesized that reducing the production of A? in the brain may slow the progression of Alzheimer disease. Therefore, different ?-secretase inhibitors have been developed to reduce A? production. Paradoxically, it has been shown that low to moderate inhibitor concentrations cause a rise in A? production in different cell lines, in different animal models, and also in humans. A mechanistic understanding of the A? rise remains elusive. Here, a minimal mathematical model has been developed that quantitatively describes the A? dynamics in cell lines that exhibit the rise as well as in cell lines that do not. The model includes steps of APP processing through both the so-called amyloidogenic pathway and the so-called non-amyloidogenic pathway. It is shown that the cross-talk between these two pathways accounts for the increase in A? production in response to inhibitor, i.e. an increase in C99 will inhibit the non-amyloidogenic pathway, redirecting APP to be cleaved by ?-secretase, leading to an additional increase in C99 that overcomes the loss in ?-secretase activity. With a minor extension, the model also describes plasma A? profiles observed in humans upon dosing with a ?-secretase inhibitor. In conclusion, this mechanistic model rationalizes a series of experimental results that spans from in vitro to in vivo and to humans. This has important implications for the development of drugs targeting A? production in Alzheimer disease. This model is hosted on BioModels Database and identified by: BIOMD0000000556. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

DISEASE(S): Alzheimer's Disease

SUBMITTER: Audald Lloret i Villas  

PROVIDER: BIOMD0000000556 | BioModels | 2014-10-23

REPOSITORIES: BioModels

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Publications

Interplay between α-, β-, and γ-secretases determines biphasic amyloid-β protein level in the presence of a γ-secretase inhibitor.

Ortega Fernando F   Stott Jonathan J   Visser Sandra A G SA   Bendtsen Claus C  

The Journal of biological chemistry 20121114 2


Amyloid-β (Aβ) is produced by the consecutive cleavage of amyloid precursor protein (APP) first by β-secretase, generating C99, and then by γ-secretase. APP is also cleaved by α-secretase. It is hypothesized that reducing the production of Aβ in the brain may slow the progression of Alzheimer disease. Therefore, different γ-secretase inhibitors have been developed to reduce Aβ production. Paradoxically, it has been shown that low to moderate inhibitor concentrations cause a rise in Aβ production  ...[more]

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