Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα.
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.
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.
Hong
H
Jiang
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.
Ping
P
He
Department of Physiology, Medical College of Qingdao University, Qingdao, China.
Junxia
J
Xie
Novartis Pharma Ltd., Nervous System Research, CH-4002 Basel, Switzerland.
Matthias
M
Staufenbiel
Center for Hormone Advanced Science and Education, Roskamp Institute, Sarasota, FL 34243, USA and yshen@rfdn.org rli@rfdn.org.
Rena
R
Li
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.
Yong
Y
Shen
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D004195:Disease Models, Animal; D017353:Gene Deletion; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D047889:Receptors, Tumor Necrosis Factor, Type II; D000072000:NF-KappaB Inhibitor alpha; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human