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

作者：He Ping; Zhong Zhenyu; Lindholm Kristina; Berning Lilian; Lee Wendy; Lemere Cynthia; Staufenbiel Matthias; Li Rena; Shen Yong^*

来源：The Journal of Cell Biology, 2007, 178(5): 829-841.

DOI：10.1083/jcb.200705042

he 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 beta protein (A)induced neuronal death. However, the function of TNFR1 in A beta plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (A beta) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1(-/-)) inhibits A beta generation and diminishes A beta plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced p-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 neuroclegeneration but also that it is involved in APP processing and A beta plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.

• 出版日期2007-8-27