Differential regulation of BACE1 promoter activity by nuclear factor-κB in neurons and glia upon exposure to β-amyloid peptides

Krystyn Z. Bourne, Diana C. Ferrari, Christine Lange-Dohna, Steffen Roßner, Thomas G. Wood, J. Regino Perez-Polo

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141 Scopus citations

Abstract

The brains of Alzheimer's disease (AD) patients display cerebrovascular and parenchymal deposits of β-amyloid (Aβ) peptides, which are derived by proteolytic processing by the β-site APP-cleaving enzyme 1 (BACE1) of the amyloid precursor protein (APP). The rat BACE1 promoter has a nuclear factor-κB (NF-κB) binding site. Deletion studies with a BACE1 promoter/luciferase reporter suggest that the NF-κB binding DNA consensus sequence plays a suppressor role, when occupied by NF-κB, in the regulation of neuronal brain BACE1 expression. Here we characterize a signal transduction pathway that may be responsible for the increases in Aβ associated with AD. We propose that the transcription factor NF-κB acts as a repressor in neurons but as an activator of BACE1 transcription in activated astrocytes present in the CNS under chronic stress, a feature present in the AD brain. The activated astrocytic stimulation of BACE1 may in part account for increased BACE1 transcription and subsequent processing of Aβ in a cell-specific manner in the aged and AD brain. As measured by reporter gene promoter constructs and endogenous BACE1 protein expression, a functional NF-κB site was stimulatory in activated astrocytes and Aβ-exposed neuronal cells and repressive in neuronal and nonactivated astrocytic cells. Given the evidence for increased levels of activated astrocytes in the aged brain, the age- and AD-associated increases in NF-κB in brain may be significant contributors to increases in Aβ, acting as a positive feedback loop of chronic inflammation, astrocyte activation, increased p65/p50 activation of BACE1 transcription, and further inflammation.

Original languageEnglish (US)
Pages (from-to)1194-1204
Number of pages11
JournalJournal of Neuroscience Research
Volume85
Issue number6
DOIs
StatePublished - May 1 2007

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Keywords

  • Alzheimer's disease
  • Astrocytes
  • BACE1
  • NF-κB

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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