Dataset Information

Das2010 - Effect of a gamma-secretase inhibitor on Amyloid-beta dynamics

ABSTRACT: Das2010 - Effect of a gamma-secretase inhibitor on Amyloid-beta dynamics This model is described in the article: Modeling effect of a ?-secretase inhibitor on amyloid-? dynamics reveals significant role of an amyloid clearance mechanism. Das R, Nachbar RB, Edelstein-Keshet L, Saltzman JS, Wiener MC, Bagchi A, Bailey J, Coombs D, Simon AJ, Hargreaves RJ, Cook JJ. Bull. Math. Biol. 2011 Jan; 73(1): 230-247 Abstract: Aggregation of the small peptide amyloid beta (A?) into oligomers and fibrils in the brain is believed to be a precursor to Alzheimer's disease. A? is produced via multiple proteolytic cleavages of amyloid precursor protein (APP), mediated by the enzymes ?- and ?-secretase. In this study, we examine the temporal dynamics of soluble (unaggregated) A? in the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys treated with different oral doses of a ?-secretase inhibitor. A dose-dependent reduction of A? concentration was observed within hours of drug ingestion, for all doses tested. A? concentration in the CSF returned to its predrug level over the monitoring period. In contrast, A? concentration in the plasma exhibited an unexpected overshoot to as high as 200% of the predrug concentration, and this overshoot persisted as late as 72 hours post-drug ingestion. To account for these observations, we proposed and analyzed a minimal physiological model for A? dynamics that could fit the data. Our analysis suggests that the overshoot arises from the attenuation of an A? clearance mechanism, possibly due to the inhibitor. Our model predicts that the efficacy of A? clearance recovers to its basal (pretreatment) value with a characteristic time of >48 hours, matching the time-scale of the overshoot. These results point to the need for a more detailed investigation of soluble A? clearance mechanisms and their interaction with A?-reducing drugs. This model is hosted on BioModels Database and identified by: BIOMD0000000551. 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: BIOMD0000000551 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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	BIOMD0000000551?filename=BIOMD0000000551-biopax2.owl	Owl
	BIOMD0000000551?filename=BIOMD0000000551-biopax3.owl	Owl
	BIOMD0000000551?filename=BIOMD0000000551-matlab.m	Other
	BIOMD0000000551?filename=BIOMD0000000551-octave.m	Other
	BIOMD0000000551?filename=BIOMD0000000551.m	Other

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Modeling effect of a γ-secretase inhibitor on amyloid-β dynamics reveals significant role of an amyloid clearance mechanism.

Das Raibatak R Nachbar Robert B RB Edelstein-Keshet Leah L Saltzman Jeffrey S JS Wiener Matthew C MC Bagchi Ansuman A Bailey James J Coombs Daniel D Simon Adam J AJ Hargreaves Richard J RJ Cook Jacquelynn J JJ

Bulletin of mathematical biology 20100422 1

Aggregation of the small peptide amyloid beta (Aβ) into oligomers and fibrils in the brain is believed to be a precursor to Alzheimer's disease. Aβ is produced via multiple proteolytic cleavages of amyloid precursor protein (APP), mediated by the enzymes β- and γ-secretase. In this study, we examine the temporal dynamics of soluble (unaggregated) Aβ in the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys treated with different oral doses of a γ-secretase inhibitor. A dose-dependent reduc ...[more]

PMID: 20411345

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Project description: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.

Project description:Î³-secretase is an intra-membrane-cleaving aspartyl protease implicated in the processing of a wide range of type I membrane proteins including the Notch receptor and the amyloid-Î² precursor protein (APP). It thus regulates a diverse array of cellular and biological processes including the differentiation of neuronal embryonic stem cells, or intestinal stem cells, with the latter controlling the self-renewing of the intestinal epithelium. Indeed, proteolysis of these proteins by Î³-secretase triggers signaling cascades by releasing intracellular domains (ICDs) which, following association with adaptor proteins and nuclear translocation, modulate the transcription of different genes by binding directly to their promoters. The pronounced proliferative and regenerative effects of Notch signaling and its implication in the generation of the AÎ²-peptides, makes Î³-secretase a therapeutic target for several types of cancer and for Alzheimerâs disease. To investigate the broad effects of Î³-secretase activity onto the cellular transcriptome, Chinese hamster ovary (CHO) cells with enhanced Î³-secretase were compared to cells with abolished Î³-secretase activity via a microarray designed for a genetically close species, mouse. Our findings will potentially help to decipher the biology of Î³-secretase, including a better understanding of the roles of this enzyme in gene transcription. We compared the transcriptomes of two CHO cell lines displaying extreme differences in Î³-secretase activity. The S-1 cell line overexpressed the four components of Î³-secretase (NCT, APH1aL, PS1, and PEN2) and was characterized by a marked increase in the level of PS1 heterodimers associated with 8-fold increased Î³-secretase activity compared to untransfected controls. The other cell line consisted of wild type CHO cells incubated with DAPT, a well-known Î³-secretase inhibitor. The two cell lines were used in combination with a mouse microarray to analyze gene transcription under enhanced Î³-secretase. Two samples, S1 and DAPT treated CHO- were used in biological triplicates each.