Sci. STKE, 4 September 2007
Neuroscience TNF and Alzheimers Disease
John F. Foley
Sciences STKE, AAAS, Washington, DC 20005, USA
Alzheimers disease (AD) is associated with the accumulation in the brain of plaques of amyloid protein (A), which is produced by the processing of amyloid precursor protein (APP) by the enzymes -secretase (BACE1) and -secretase. He et al. pursued their earlier finding that overexpression of tumor necrosis factor (TNF) receptor 1 (TNFR1) promoted A-induced neuronal death by examining the role of TNFR1 in A production. They crossed transgenic APP23 mice, which express a mutant APP and develop A plaques, with TNFR1–/– mice (APP23/TNFR1–/–). Immunhistochemical analyses of the brains of 14-month-old animals showed a decreased number and size of A plaques in APP23/TNFR1–/– mice compared with those in APP23 mice. Real-time reverse transcription polymerase chain reaction assays, together with Western blotting, showed that the abundance of BACE1 mRNA and protein were lower in APP23/TNFR1–/– mice compared with APP23 mice, which suggests that TNFR1 signaling promotes the production of BACE1. Experiments in 293 cells transfected with a reporter plasmid showed that TNF- treatment induced BACE1 promoter activity, which was blocked by a specific inhibitor of the transcription factor nuclear factor B (NF-B). Immunohistochemistry demonstrated the presence of fewer neurons in the brains of APP23 mice than in brains from APP23/TNFR1–/– mice. In learning and object recognition tests, APP23 mice performed poorly; APP23/TNFR1–/– mice performed better, with abilities similar to those of wild-type mice. Together, these data implicate TNFR1 in promoting abnormal APP processing, A plaque formation, and learning defects and suggest that TNFR1 might be an effective therapeutic target in treating AD.
P. He, Z. Zhong, K. Lindholm, L. Berning, W. Lee, C. Lemere, M. Staufenbiel, R. Li, Y. Shen, Deletion of tumor necrosis factor death receptor inhibits amyloid generation and prevents learning and memory deficits in Alzheimers mice. J. Cell Biol. 178, 829-841 (2007). [Abstract] [Full Text]
Citation: J. F. Foley, TNF and Alzheimers Disease. Sci. STKE 2007, tw320 (2007).
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