Cellular and Molecular Neurobiology

, Volume 34, Issue 3, pp 315–322 | Cite as

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
Short Communication

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.

Keywords

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

Abbreviations

AD

Alzheimer’s disease

UPS

Ubiquitin-proteasome system

GFPu

Green fluorescence reporter for UPS functionality

APP

Amyloid precursor protein

PS

Presenilin

NFT

Neurofibrillary tangle

PolyUb

Polyubiquitin

Tg

Transgenic

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Yanying Liu
    • 1
  • Casey L. Hettinger
    • 1
  • Dong Zhang
    • 1
  • Khosrow Rezvani
    • 1
  • Xuejun Wang
    • 1
  • Hongmin Wang
    • 1
  1. 1.Division of Basic Biomedical Sciences, Sanford School of MedicineUniversity of South DakotaVermillionUSA

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