title: Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice.
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 beta protein (Abeta)-induced neuronal death. However, the function of TNFR1 in Abeta 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 Abeta generation and diminishes Abeta plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced beta-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-kappaB 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 Abeta plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.
authors.affiliation: Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhong
authors.forename: Kristina
authors.initials: K
authors.lastname: Lindholm
authors.forename: Lilian
authors.initials: L
authors.lastname: Berning
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lemere
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Rena
authors.initials: R
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism; D007858:Learning / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D015260:Neprilysin; D007339:Insulysin