Editors' ChoiceNeuroscience

TNF and Alzheimer’s Disease

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Science's STKE  04 Sep 2007:
Vol. 2007, Issue 402, pp. tw320
DOI: 10.1126/stke.4022007tw320

Alzheimer’s disease (AD) is associated with the accumulation in the brain of plaques of amyloid β protein (Aβ), which is produced by the processing of amyloid precursor protein (APP) by the enzymes β-secretase (BACE1) and γ-secretase. He et al. pursued their earlier finding that overexpression of tumor necrosis factor (TNF) receptor 1 (TNFR1) promoted Aβ-induced neuronal death by examining the role of TNFR1 in Aβ production. They crossed transgenic APP23 mice, which express a mutant APP and develop Aβ plaques, with TNFR1–/– mice (APP23/TNFR1–/–). Immunhistochemical analyses of the brains of 14-month-old animals showed a decreased number and size of Aβ 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-α treatment induced BACE1 promoter activity, which was blocked by a specific inhibitor of the transcription factor nuclear factor κB (NF-κB). 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, Aβ 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 β generation and prevents learning and memory deficits in Alzheimer’s mice. J. Cell Biol. 178, 829-841 (2007). [Abstract] [Full Text]