Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease

Amyloid β‐peptide (Aβ) accumulation leads to neurodegeneration and Alzheimer disease; however, amyloid metabolism is a dynamic process and enzymic mechanisms exist for Aβ removal. Considerable controversy surrounds whether the intracellular domain of the amyloid precursor protein (AICD) regulates ex...

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Bibliographic Details
Published in:EMBO reports 2009-01, Vol.10 (1), p.94-100
Main Authors: Belyaev, Nikolai D, Nalivaeva, Natalia N, Makova, Natalia Z, Turner, Anthony J
Format: Article
Language:English
Subjects:
Alzheimer disease
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid beta-Protein Precursor - metabolism
amyloid β-peptide
Animals
Binding sites
Cell Line
Cellular biology
Enzyme Inhibitors - pharmacology
Gene expression
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
histone deacetylase
Histone Deacetylase Inhibitors
Histone Deacetylases - genetics
Histone Deacetylases - metabolism
Histones - metabolism
Humans
neprilysin
Neprilysin - genetics
Neprilysin - metabolism
Neurons
Peptides
Promoter Regions, Genetic - genetics
Protein Binding
Rats
Scientific Report
valproate
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Summary:Amyloid β‐peptide (Aβ) accumulation leads to neurodegeneration and Alzheimer disease; however, amyloid metabolism is a dynamic process and enzymic mechanisms exist for Aβ removal. Considerable controversy surrounds whether the intracellular domain of the amyloid precursor protein (AICD) regulates expression of the Aβ‐degrading metalloprotease, neprilysin (NEP). By comparing two neuroblastoma cell lines differing substantially in NEP expression, we show by chromatin immunoprecipitation (ChIP) that AICD is bound directly to the NEP promoter in high NEP‐expresser (NB7) cells but not in low‐expresser (SH‐SY5Y) cells. The methylation status of the NEP promoter does not regulate expression in these cells, whereas the histone deacetylase inhibitors trichostatin A and valproate partly restore NEP expression and activity in SH‐SY5Y cells. ChIP analysis also reveals AICD binding to the NEP promoter in rat primary neurons but not in HUVEC cells. Chromatin remodelling of crucial Alzheimer disease‐related genes by valproate could provide a new therapeutic strategy.
ISSN:1469-221X
1469-3178
1469-221X
DOI:10.1038/embor.2008.222