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J. Cell Biol. 178 (5): 829-841

Copyright © 2007 by the Rockefeller University Press.


Article

Deletion of tumor necrosis factor death receptor inhibits amyloid ß generation and prevents learning and memory deficits in Alzheimer's mice

Ping He1, Zhenyu Zhong1, Kristina Lindholm1, Lilian Berning1, Wendy Lee1, Cynthia Lemere3, Matthias Staufenbiel4, Rena Li2, , and Yong Shen1

1 Haldeman Laboratory of Molecular and Cellular Neurobiology and 2 Roberts Center for Alzheimer's Research, Sun Health Research Institute, Sun City, AZ 85351
3 Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
4 Novartis Pharma Ltd., Nervous System Research, CH-4002 Basel, Switzerland

Correspondence to Yong Shen: yong.shen{at}sunhealth.org

Abstract: The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid ß protein (Aß)–induced neuronal death. However, the function of TNFR1 in Aß plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1–/–) inhibits Aß generation and diminishes Aß plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced ß-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-{kappa}B pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Aß plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.

P. He and Z. Zhong contributed equally to this paper.

Abbreviations used in this paper: Aß, amyloid ß protein; AD, Alzheimer's disease; ANOVA, analysis of variance; APP, amyloid precursor protein; BACE1, ß-secretase 1; CAA, cerebral amyloid angiopathy; IDE, insulin degradation enzyme; NEP, neprilysin; NF-{kappa}B, nuclear factor {kappa}B; TNFR1, TNF type 1 death receptor; vWF, von Willebrand factor.


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