The retromer complex system in a transgenic mouse model of AD: influence of age

Publication date: Available online 3 January 2017
Source:Neurobiology of Aging
Author(s): Jin Chu, Domenico Praticò
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown.In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, CI-MRP, SorLA in brains of Tg2576 and controls at 3, 8 and 14 months of age. While cortex showed an age-dependent decrease in all but VPS29, levels of the same proteins in the cerebellum were unchanged at any age. Neuronal cells expressing human APP Swedish mutant had also reduced retromer complex levels. However, incubation with a pharmacological chaperone dose-dependently restored these levels together with a reduction in Aβ.Our study is the first to show that in a transgenic mouse model of AD the changes in the expression levels of the retromer complex are age and region-dependent, and that the complex is a viable therapeutic target since its deficiency can be restored pharmacologically by a retromer chaperone.



http://ift.tt/2hMiZuG