title: The retromer complex system in a transgenic mouse model of AD: influence of age.
abstract: 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, cation independent mannose 6-phosphate receptor, sortilin-related receptor in brains of Tg2576 and controls at the ages of 3, 8, and 14 months. 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 amyloid beta precursor protein Swedish mutant had also reduced retromer complex levels. However, incubation with a pharmacological chaperone dose-dependently restored these levels together with a reduction in amyloid beta. 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.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA. Electronic address: praticod@temple.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000494:pharmacology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D017527:Receptor, IGF Type 2; C503111:VPS29 protein, mouse; D033921:Vesicular Transport Proteins; C089989:Vps26 protein, mouse; C101274:Vps35 protein, mouse
keywords: Alzheimer's disease; Amyloid beta; Amyloid beta precursor protein; Retromer complex; Transgenic mice; Vacuolar protein sorting system