Mutant ubiquitin decreases amyloid ¦Â plaque formation in a transgenic mouse model of Alzheimer¡¯s disease

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• 作者：Paula van Tijn ; Frank J.A. Dennissen ; Romina J.G. Gentier ; Barbara Hobo ; Denise Hermes ; Harry W.M. Steinbusch ; Fred W. Van Leeuwen ; David F. Fischer
• 关键词：Alzheimer&rsquo ; s disease ; Amyloid ¦Â ; UBB+1 ; Ubiquitin&ndash ; proteasome system
• 刊名：Neurochemistry International
• 出版年：2012
• 出版时间：October, 2012
• 年：2012
• 卷：61
• 期：5
• 页码：739-748
• 全文大小：1272 K

文摘

The mutant ubiquitin UBBp>+1p> is a substrate as well as an inhibitor of the ubiquitin-proteasome system (UPS) and accumulates in the neuropathological hallmarks of Alzheimer¡¯s disease (AD). A role for the UPS has been suggested in the generation of amyloid ¦Â (A¦Â) plaques in AD. To investigate the effect of UBBp>+1p> expression on amyloid pathology in vivo, we crossed UBBp>+1p> transgenic mice with a transgenic line expressing AD-associated mutant amyloid precursor protein (APPSwe) and mutant presenilin 1 (PS1dE9), resulting in APPPS1/UBBp>+1p> triple transgenic mice. In these mice, we determined the A¦Â levels at 3, 6, 9 and 11 months of age. Surprisingly, we found a significant decrease in A¦Â deposition in amyloid plaques and levels of soluble A¦Â₄₂ in APPPS1/UBBp>+1p> transgenic mice compared to APPPS1 mice at 6 months of age, without alterations in UBBp>+1p> protein levels or proteasomal chymotrypsin activity. These lowering effects of UBBp>+1p> on A¦Â deposition were transient, as this relative decrease in plaque load was not significant in APPPS1/UBBp>+1p> mice at 9 and 11 months of age. We also show that APPPS1/UBBp>+1p> mice exhibit astrogliosis, indicating that they may not be improved functionally compared to APPPS1 mice despite the A¦Â reduction. The molecular mechanism underlying this decrease in A¦Â deposition in APPPS1/UBBp>+1p> mice is more complex than previously assumed because UBBp>+1p> is also ubiquitinated at K63 opening the possibility of additional effects of UBBp>+1p> (e.g. kinase activation).