Aβ inhibits the proteasome and enhances amyloid and tau accumulation

NEUROBIOLOGY OF AGING

卷:29

Article

Tseng, Bertrand P.¹  Green, Kim N.¹  Chan, Julie L.¹  Blurton-Jones, Mathew¹  LaFerla, Frank M.¹ 

[1] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA

关键词: proteasome;    Alzheimer's disease;    amyloid beta;    tau;    transgenic;    oliogmers;    immunotherapy;   

DOI  :  10.1016/j.neurobiolaging.2007.04.014

来源: Elsevier

【 摘 要 】

The accumulation of misfolded protein aggregates is a common feature of numerous neurodegenerative disorders including Alzheimer disease (AD). Here, we examined the effects of different assembly states of amyloid beta (A beta) on proteasome function. We find that A beta oligomers, but not monomers, inhibit the proteasome in vitro. In young 3xTg-AD mice, we observed impaired proteasome activity that correlates with the detection of intraneuronal A beta oligomers. Blocking proteasome function in pre-pathological 3xTg-AD mice with specific inhibitors causes a marked increase in A beta and tau accumulation, highlighting the adverse consequences of impaired proteasome activity for AD. Lastly, we show that A beta immunotherapy in the 3xTg-AD mice reduces A beta oligomers and reverses the deficits in proteasome activity. Taken together, our results indicate that A beta oligomers impair proteasome activity, contributing to the age-related pathological accumulation of A beta and tau. These findings provide further evidence that the proteasome represents a viable target for therapeutic intervention in AD. Published by Elsevier Inc.

【 授权许可】

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