Modeling of age-dependent amyloid accumulation and ?-secretase inhibition of soluble and insoluble A? in a transgenic mouse model of amyloid deposition.

ABSTRACT: According to the "amyloid hypothesis," accumulation of amyloid beta (A?) peptides in the brain is linked to the development of Alzheimer's disease. The aims of this investigation were to develop a model for the age-dependent amyloid accumulation and to quantify the age- and treatment-duration-dependent efficacy of the ?-secretase inhibitor MRK-560 in the Tg2576 transgenic mouse model of amyloid deposition. Soluble and insoluble A?40 and A?42 brain concentrations were compiled from multiple naïve, vehicle, and MRK-560-treated animals. The age of Tg2576 mice in the studies ranged between 3.5 and 26 months. Single doses of MRK-560 inhibited soluble A?40 levels in animals up to 9 months old. In contrast, MRK-560 did not cause significant acute effects on soluble A?40 levels in animals older than 13 months. Absolute levels of A? variants increased exponentially over age and reached a plateau at ?20 months. In the final model, it was assumed that MRK-560 inhibited the A? production rate with an A? level-dependent IC50.The age-dependent increase in A? levels was best described by a logistic model that stimulated the production rate of soluble A?. The increase in insoluble A? was defined as a function of soluble A? by using a scaling factor and a different turnover rate. The turnover half-life for insoluble A? was estimated at 30 days, explaining that at least a 4-week treatment in young animals was required to demonstrate a reduction in insoluble A?. Taken together, the derived knowledge could be exploited for an improved design of new experiments in Tg2576 mice.

SUBMITTER: Parkinson J 

PROVIDER: S-EPMC4186430 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature