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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alzheimer Disease* / genetics
-
Alzheimer Disease* / metabolism
-
Alzheimer Disease* / pathology
-
Alzheimer Disease* / physiopathology
-
Amyloid Precursor Protein Secretases / genetics
-
Amyloid Precursor Protein Secretases / metabolism
-
Amyloid beta-Peptides / genetics
-
Amyloid beta-Peptides / metabolism*
-
Animals
-
Aspartic Acid Endopeptidases / genetics
-
Aspartic Acid Endopeptidases / metabolism
-
Behavior, Animal / physiology
-
Cerebral Amyloid Angiopathy / genetics
-
Cerebral Amyloid Angiopathy / pathology
-
Cerebral Amyloid Angiopathy / physiopathology
-
Disease Models, Animal
-
Gene Deletion*
-
Gene Expression Regulation
-
Humans
-
Insulysin / genetics
-
Insulysin / metabolism
-
Learning / physiology*
-
Memory Disorders* / genetics
-
Memory Disorders* / metabolism
-
Memory Disorders* / physiopathology
-
Mice
-
Mice, Knockout
-
Mice, Transgenic
-
Microglia / cytology
-
Microglia / metabolism
-
NF-kappa B / metabolism
-
Neprilysin / genetics
-
Neprilysin / metabolism
-
Neurons / cytology
-
Neurons / metabolism
-
Promoter Regions, Genetic
-
Receptors, Tumor Necrosis Factor, Type I / genetics
-
Receptors, Tumor Necrosis Factor, Type I / metabolism*
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
Amyloid beta-Peptides
-
NF-kappa B
-
Receptors, Tumor Necrosis Factor, Type I
-
Tumor Necrosis Factor-alpha
-
Amyloid Precursor Protein Secretases
-
Aspartic Acid Endopeptidases
-
Bace1 protein, mouse
-
Neprilysin
-
Insulysin