title: The proteasome function reporter GFPu accumulates in young brains of the APPswe/PS1dE9 Alzheimer's disease mouse model.
abstract: Alzheimer's disease (AD), the most common cause of dementia, is neuropathologically characterized by accumulation of insoluble fibrous inclusions in the brain in the form of intracellular neurofibrillary tangles and extracellular senile plaques. Perturbation of the ubiquitin-proteasome system (UPS) has long been considered an attractive hypothesis to explain the pathogenesis of AD. However, studies on UPS functionality with various methods and AD models have achieved non-conclusive results. To get further insight into UPS functionality in AD, we have crossed a well-documented APPswe/PS1dE9 AD mouse model with a UPS functionality reporter, GFPu, mouse expressing green fluorescence protein (GFP) fused to a constitutive degradation signal (CL-1) that facilitates its rapid turnover in conditions of a normal UPS. Our western blot results indicate that GFPu reporter protein was accumulated in the cortex and hippocampus, but not striatum in the APPswe/PS1dE9 AD mouse model at 4 weeks of age, which is confirmed by fluorescence microscopy and elevated levels of p53, an endogenous UPS substrate. In accordance with this, the levels of ubiquitinated proteins were elevated in the AD mouse model. These results suggest that UPS is either impaired or functionally insufficient in specific brain regions in the APPswe/PS1dE9 AD mouse model at a very young age, long before senile plaque formation and the onset of memory loss. These observations may shed new light on the pathogenesis of AD.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Liu
authors.forename: Casey L
authors.initials: CL
authors.lastname: Hettinger
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.forename: Khosrow
authors.initials: K
authors.lastname: Rezvani
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Hongmin
authors.initials: H
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics; D043743:Ubiquitin-Protein Ligase Complexes / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; C580804:presenilin 1, mouse; D049452:Green Fluorescent Proteins; D043743:Ubiquitin-Protein Ligase Complexes