Authors:
Lydia S. Glaw and Thomas C. Skalak
Summary:
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.
Source:
Journal of the Federation of American Societies for Experimental Biology; 23, 994.4 (2009)