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Hum Mol Genet. 2014 Sep 15;23(18):4906-18. doi: 10.1093/hmg/ddu206. Epub 2014 May 13.

Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα.

Author information

1
Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA, Department of Physiology, Medical College of Qingdao University, Qingdao, China.
2
Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA, Center for Advanced Therapeutic Strategies of Brain Disorders, Roskamp Institute, Sarasota, FL 34243, USA.
3
Department of Physiology, Medical College of Qingdao University, Qingdao, China.
4
Novartis Pharma Ltd., Nervous System Research, CH-4002 Basel, Switzerland.
5
Center for Hormone Advanced Science and Education, Roskamp Institute, Sarasota, FL 34243, USA and yshen@rfdn.org rli@rfdn.org.
6
Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA, Department of Physiology, Medical College of Qingdao University, Qingdao, China, Center for Advanced Therapeutic Strategies of Brain Disorders, Roskamp Institute, Sarasota, FL 34243, USA yshen@rfdn.org rli@rfdn.org.

Abstract

Tumor necrosis factor receptor II (TNFRII) is one of the TNF receptor superfamily members and our recent pathological studies show that TNFRII is deficient in the brains of Alzheimer's disease (AD). However, the mechanisms of TNFRII in AD pathogenesis remain unclear. In the present study, by using the gene-targeting approach to delete TNFRII in AD transgenic mouse model, we found that, in the brain of APP23 mice with TNFRII deletion (APP23/TNFRII(-/-)), AD-like pathology, i.e. plaque formation and microglial activation, occurs as early as 6 months of age. To test whether the increased levels of Aβ plaques was due to elevated Aβ, we measured Aβ and found that Aβ levels indeed were significantly increased at this age. Because β-secretase, BACE1, is critical enzyme for Aβ production, we have examined BACE1 and found that BACE1 is increased in both protein levels and enzymatic activity as early as 6 months of age; Having shown that BACE1 promoter region contains NF-κB binding sites, we found that cytoplasmic NF-κB was elevated and SUMO1 binding to IκBα was decreased. To further verify these findings, we have overexpressed TNFRII and identified that overexpressing TNFRII can reverse the findings from APP23/TNFRII(-/-) mice. Altogether, our results demonstrate novel roles of TNFRII in the regulation of Aβ production, suggesting a potential therapeutic strategy for AD by up-regulating TNFRII levels and elevating phosphorylated IκBα by SUMOylation.

PMID:
24824215
PMCID:
PMC4148612
DOI:
10.1093/hmg/ddu206
[Indexed for MEDLINE]
Free PMC Article
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