Neurological side effects due to GSK-3 inhibition by chronic lithium or transgenesis can be prevented by blocking NFAT/Fas pathway

Abstract

cognitive measures it is important to assess the effect of different amyloidbeta conformations on brain network emergent properties, such as memory trace stability. Methods: The functional effects of different amyloid-beta conformations are studied in a well calibrated computer-based mechanistic disease model of the human cortex. The system of 120 biophysically realistic neurons is based upon preclinical physiology data in rodents and primates, but parametrized using human pathology and pharmacology data. The physiology of 29 different CNS targets, such as DA, 5-HT, NE and cholinergic receptors is added. After implementing broad AD pathology from human imaging data, the stability of a memory trace is calibrated with clinical ADASCog readouts of 28 clinical interventions. Results: Dose-responses of various symptomatic treatment effects with dopamine, serotoninergic and cholinergic targets suggest an improvement of the stability at 12 and 26 weeks, but not in more severe disease states. The effect of amyloid-beta is complex, resulting often in an inverse U-shape dose-response. Close inspection reveals that the balance between excitation and inhibition in cortical networks is crucial in maintaining a functional cognitive network. This observation suggests that there is an optimal strategy for each different state of the disease.Conclusions: This humanized translational ‘in silico cognition’ approach in general can become a useful tool in the discovery and development of new therapeutics in AD, by addressing issues such as a different pharmacology of the clinical candidate for human vs rodent targets, off-target effects that mediate functional outcome and unique human metabolites.