Abstract
Accumulation of the amyloid-beta peptide (Abeta) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, has been correlated in vivo with Abeta accumulation in transgenic mice and recently with Abeta clearance by activated microglia. Here, we demonstrate that TGF-beta1 drives the production of Abeta40/42 by astrocytes leading to Abeta production in TGF-beta1 transgenic mice. First, TGF-beta1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-beta1-responsive element in the 5'-untranslated region (+54/+74) of the APP promoter. Second, we demonstrated an increased release of soluble APP-beta which led to TGF-beta1-induced Abeta generation in both murine and human astrocytes. These results demonstrate that TGF-beta1 potentiates Abeta production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / metabolism
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Amyloid beta-Peptides / chemistry*
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Amyloid beta-Protein Precursor / genetics
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Animals
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Astrocytes / cytology
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Astrocytes / metabolism
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Base Sequence
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Blotting, Western
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Cell Nucleus / metabolism
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Cells, Cultured
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Culture Media, Conditioned / pharmacology
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Densitometry
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Enzyme-Linked Immunosorbent Assay
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Genes, Reporter
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Humans
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Immunoblotting
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Immunohistochemistry
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Luciferases / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Microglia / metabolism
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Microscopy, Fluorescence
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Molecular Sequence Data
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Neurons / metabolism
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Promoter Regions, Genetic
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Time Factors
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Transcription Factors
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Transfection
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Transforming Growth Factor beta / chemistry
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta1
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Transgenes
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Culture Media, Conditioned
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RNA, Messenger
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Transcription Factors
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Luciferases