Abstract
It is widely believed that one of the causes of Alzheimer's disease (AD) is the generation and secretion of beta-amyloid (Abeta) from amyloid precursor protein in the brain. Here we report that a transcription factor, NF-kappaB/p65, induces increased secretion of amyloidogenic Abeta42 but not Abeta40. The kappaB motif-dependent production of Abeta42 was suppressed by binding of NF-kappaB/p65 to the PDZ domain of the X11-like protein (X11L), which a human homologue protein of LIN-10. The results suggest that the PDZ domain of X11L can control the ability of NF-kappaB/p65 to induce expression of protein(s) involved in Abeta42 production. The amino acids 161-163 in Rel homology domain (RHD) of NF-kappaB/p65 is important in interaction of NF-kappaB/p65 with X11L. Another subunit NF-kappaB/p50 and heterodimers of p65 and p50 do not bind to X11L. Our finding indicates NF-kappaB and X11L may, in novel way, regulate Abeta production in neuronal cells. Targeting X11L by specific therapy may provide the possibility to control the progression of AD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Alzheimer Disease / metabolism
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Brain / metabolism
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COS Cells
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Cell Line
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DNA, Complementary / metabolism
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Gene Expression Regulation
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Gene Library
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Humans
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Luciferases / metabolism
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NF-kappa B / chemistry
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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NF-kappa B p50 Subunit
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / metabolism*
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Neurons / metabolism*
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Precipitin Tests
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Protein Binding
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Protein Isoforms
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Protein Structure, Tertiary
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Transcription Factor RelA
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Transcription, Genetic
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Transfection
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Two-Hybrid System Techniques
Substances
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APBA1 protein, human
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Adaptor Proteins, Signal Transducing
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Amyloid beta-Peptides
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DNA, Complementary
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NF-kappa B
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NF-kappa B p50 Subunit
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Nerve Tissue Proteins
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Peptide Fragments
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Protein Isoforms
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Transcription Factor RelA
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Luciferases