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A computational model of the role of presenilin‐1 and glycogen synthase kinase‐3 in familial Alzheimer's disease
Author(s) -
Glaw Lydia S.,
Skalak Thomas C.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.994.4
Subject(s) - gsk 3 , presenilin , glycogen synthase , gsk3b , tangle , amyloid precursor protein , phosphorylation , alzheimer's disease , neurofibrillary tangle , pi3k/akt/mtor pathway , protein kinase b , chemistry , neuroscience , disease , biology , microbiology and biotechnology , biochemistry , senile plaques , signal transduction , medicine , mathematics , pure mathematics
Familial Alzheimer's disease (FAD) has been linked to mutations in presenilin‐1 (PS1), presenilin‐2 (PS2), and amyloid precursor protein (APP). Also, interest has recently developed in the possibility of a role for glycogen synthase kinase‐3 (GSK‐3) as a mediator of both amyloid beta (Aβ) plaque and neurofibrillary tangle development, the two hallmarks of Alzheimer's. We constructed a computational model of key signaling pathways to quantitatively examine the roles of both PS1 and GSK‐3 in the development of FAD pathology. This model consists of a series of kinetic equations describing the interactions of proteins and complexes including gamma secretase, APP, phosphoinositide kinase‐3 (PI3K), and tau, with outputs of the ratios of Aβ42 to Aβ40 and phosphorylated to unphosphorylated tau. Model predictions for the non‐disease state are in good agreement with experimental data. Notably, the interaction of PS1 with the PI3K‐Akt pathway is not predicted to significantly affect the rate of tau phosphorylation by GSK‐3. Findings produced by this model should provide an experimental roadmap for researchers in the field.