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Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease
Author(s) -
Belyaev Nikolai D,
Nalivaeva Natalia N,
Makova Natalia Z,
Turner Anthony J
Publication year - 2009
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2008.222
Subject(s) - neprilysin , chromatin immunoprecipitation , trichostatin a , neurodegeneration , amyloid precursor protein , biology , microbiology and biotechnology , chromatin , promoter , intracellular , gene expression , histone deacetylase , alzheimer's disease , histone , gene , biochemistry , medicine , enzyme , 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 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.