Modeling effect of a γ-secretase inhibitor on amyloid-ß dynamics reveals significant role of an amyloid clearance mechanism.
Bull Math Biol
; 73(1): 230-47, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-20411345
ABSTRACT
Aggregation of the small peptide amyloid beta (Aß) into oligomers and fibrils in the brain is believed to be a precursor to Alzheimer's disease. Aß is produced via multiple proteolytic cleavages of amyloid precursor protein (APP), mediated by the enzymes ß- and γ-secretase. In this study, we examine the temporal dynamics of soluble (unaggregated) Aß in the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys treated with different oral doses of a γ-secretase inhibitor. A dose-dependent reduction of Aß concentration was observed within hours of drug ingestion, for all doses tested. Aß concentration in the CSF returned to its predrug level over the monitoring period. In contrast, Aß 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 Aß dynamics that could fit the data. Our analysis suggests that the overshoot arises from the attenuation of an Aß clearance mechanism, possibly due to the inhibitor. Our model predicts that the efficacy of Aß 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 Aß clearance mechanisms and their interaction with Aß-reducing drugs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Secretases da Proteína Precursora do Amiloide
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Modelos Biológicos
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article