The proteasome function reporter GFPu accumulates in young brains of the APPswe/PS1dE9 Alzheimer's disease mouse model

Yanying Liu, Casey L. Hettinger, Dong Zhang, Khosrow Rezvani, Xuejun Wang, Hongmin Wang

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)315-322
Number of pages8
JournalCellular and molecular neurobiology
Volume34
Issue number3
DOIs
StatePublished - Apr 2014

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Keywords

  • Alzheimer disease
  • GFPu
  • Proteasome function reporter
  • Protein degradation
  • Ubiquitin-proteasome system
  • Ubiquitinated proteins

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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