title: Modeling of age-dependent amyloid accumulation and γ-secretase inhibition of soluble and insoluble Aβ in a transgenic mouse model of amyloid deposition.
abstract: According to the "amyloid hypothesis," accumulation of amyloid beta (Aβ) 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 γ-secretase inhibitor MRK-560 in the Tg2576 transgenic mouse model of amyloid deposition. Soluble and insoluble Aβ40 and Aβ42 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 Aβ40 levels in animals up to 9 months old. In contrast, MRK-560 did not cause significant acute effects on soluble Aβ40 levels in animals older than 13 months. Absolute levels of Aβ variants increased exponentially over age and reached a plateau at ∼20 months. In the final model, it was assumed that MRK-560 inhibited the Aβ production rate with an Aβ level-dependent IC50.The age-dependent increase in Aβ levels was best described by a logistic model that stimulated the production rate of soluble Aβ. The increase in insoluble Aβ was defined as a function of soluble Aβ by using a scaling factor and a different turnover rate. The turnover half-life for insoluble Aβ was estimated at 30 days, explaining that at least a 4-week treatment in young animals was required to demonstrate a reduction in insoluble Aβ. Taken together, the derived knowledge could be exploited for an improved design of new experiments in Tg2576 mice.
authors.affiliation: Primary laboratory of origin, AstraZeneca R&D CNSP Innovative Medicines SE-15185, Södertälje, Sweden.
authors.forename: Joanna
authors.initials: J
authors.lastname: Parkinson
authors.affiliation: Primary laboratory of origin, AstraZeneca R&D CNSP Innovative Medicines SE-15185, Södertälje, Sweden.
authors.forename: Bart
authors.initials: B
authors.lastname: Ploeger
authors.affiliation: Primary laboratory of origin, AstraZeneca R&D CNSP Innovative Medicines SE-15185, Södertälje, Sweden.
authors.forename: Paulina
authors.initials: P
authors.lastname: Appelkvist
authors.affiliation: Primary laboratory of origin, AstraZeneca R&D CNSP Innovative Medicines SE-15185, Södertälje, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Bogstedt
authors.affiliation: Primary laboratory of origin, AstraZeneca R&D CNSP Innovative Medicines SE-15185, Södertälje, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Dillner Bergstedt
authors.affiliation: Primary laboratory of origin, AstraZeneca R&D CNSP Innovative Medicines SE-15185, Södertälje, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Eketjäll
authors.affiliation: Primary laboratory of origin, AstraZeneca R&D CNSP Innovative Medicines SE-15185, Södertälje, Sweden.
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
keywords: Alzheimer's disease; Aβ; Tg2576 mouse; disease progression; modeling; pharmacokinetic-pharmacodynamic; γ-secretase inhibitor