Systems pharmacology of the amyloid cascade : unfolding oligomer modulation in Alzheimer's disease

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Systems pharmacology of the amyloid cascade : unfolding oligomer modulation in Alzheimer's disease

Type: Doctoral Thesis
Title: Systems pharmacology of the amyloid cascade : unfolding oligomer modulation in Alzheimer's disease
Author: Maanen, E.M.T. van
Issue Date: 2017-11-23
Keywords: Systems pharmacology
Alzheimer's Disease
Amyloid cascade hypothesis
amyloid-beta
NONMEM
Abeta oligomers
Abstract: According to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD). Early in the disease process, before clinical symptoms, an increase in Aβ concentrations leads to formation of toxic Aβ oligomers. These oligomers drive the neurodegeneration in AD brain. An important therapeutic strategy is to lower Aβ concentration in the CNS. Theoretically, this can prevent all subsequent pathological processes. Aβ is the final product of sequential proteolytic cleavages of the precursor protein APP. The drug effects on the individual pathways of APP processing are hard to predict, because these are regulated by a complex biochemical network. In this research, a 'systems pharmacology' approach was applied, integrating available knowledge of biology and pharmacology of system reactions into mathematical models. The APP-system-pharmacology-model provides important information about the APP processing pathways: (i) Aβ production inhibition leads to a relatively greater decrease in Aβ oligomers compared to monomers (ii) dissociation of oligomers contributes to the drug effect; (iii) Aβ42 is the major Aβ variant that contributes to the oligomer pool; (iv) inhibition of the enzyme GS stimulates alternative processing of APP by feedback. The APP-system-pharmacology-model can be of value in development of therapeutic interventions for AD.
Promotor: Supervisor: Danhof M. Co-Supervisor: Steeg T.J. van, Stone J.A.
Faculty: Science
University: Leiden
Uri: urn:isbn:9789462997660
Handle: http://hdl.handle.net/1887/55514
 

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