Extending a Systems Model of the APP Pathway: Separation of ß- and γ-Secretase Sequential Cleavage Steps of APP.
J Pharmacol Exp Ther
; 365(3): 507-518, 2018 06.
Article
em En
| MEDLINE
| ID: mdl-29563326
ABSTRACT
The abnormal accumulation of amyloid-ß (Aß) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the amyloid precursor protein (APP) pathway, describing the Aß APP metabolite responses (Aß40, Aß42, sAPPα, and sAPPß) to ß-secretase 1 (BACE1) inhibition. In this investigation this model was challenged to describe Aß dynamics following γ-secretase (GS) inhibition. This led an extended systems pharmacology model, with separate descriptions to characterize the sequential cleavage steps of APP by BACE1 and GS, to describe the differences in Aß response to their respective inhibition. Following GS inhibition, a lower Aß40 formation rate constant was observed, compared with BACE1 inhibition. Both BACE1 and GS inhibition were predicted to lower Aß oligomer levels. Further model refinement and new data may be helpful to fully understand the difference in Aß dynamics following BACE1 versus GS inhibition.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Precursor de Proteína beta-Amiloide
/
Secretases da Proteína Precursora do Amiloide
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Proteólise
/
Modelos Biológicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article