BACE1 gene promoter is differentially regulated

Detection of a novel promoter region for its cell type-specific regulation

Debomoy Lahiri, Bryan Maloney, Yuan Wen Ge

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The amyloid-β (Aβ) peptide, the proteolytic fragment of Aβ precursor protein (APP), aggregates and forms neuritic plaques, a major hallmark of Alzheimer's disease (AD). The limiting step in generating the Aβ peptide from APP is cleavage by the β-secretase enzyme, BACE1. Regulation of the BACE1 gene is likely to play an important role in AD etiology and treatment. We therefore studied the activity of a 4.1-kb 5′-flanking region (-3765/+364, +1 being the transcription start site) of the BACE1 gene, both in 5′- and 3′-deletion series and through Northern blotting. We show that the BACE1 promoter has regulatory activity throughout the 4.1-kb length, both positive and negative, and that this activity can be quantitatively modeled according to promoter sequence length, with the specific model depending on the presence of negative regulatory elements as the 5′-most portion of the sequence. We also examined a previously identified 141-bp proximal fragment (+224/+364) of the BACE1 promoter and two constituent (91- and 50-bp) subfragments. We report that the 91-bp fragment (+224/+314) is the most likely seat of neuronal expression of the BACE1 gene and that it is the portion of the 141-bp fragment that accounts for observed DNA-protein interactions in brain extracts. The 50-bp fragment (+315/+364), which showed significant reporter gene activity from the empty vector, binds nuclear proteins in a cell type-specific manner and contains the AP2 site as shown by the electrophoretic mobility shift assay. Overall, the 141-bp fragment had no strong matches within GenBank, and the 91-bp fragment is predicted to have several potential stem-loop sites. Taken together, BACE1 gene promoter activity is differentially regulated, and the 91-bp fragment represents a novel promoter region for cell type-specific regulation. This fragment might be a useful target to regulate BACE1 expression leading to Aβ production and to understand the neuropathogenesis of AD.

Original languageEnglish
Pages (from-to)193-210
Number of pages18
JournalJournal of Molecular Neuroscience
Volume28
Issue number2
DOIs
StatePublished - 2006

Fingerprint

Genetic Promoter Regions
Alzheimer Disease
Genes
Amyloid Precursor Protein Secretases
Peptide Fragments
Protein Precursors
5' Flanking Region
Transcription Initiation Site
Nucleic Acid Databases
Amyloid Plaques
Electrophoretic Mobility Shift Assay
Nuclear Proteins
Reporter Genes
Amyloid
Northern Blotting
Electrophoretic mobility
Gene Expression
Seats
DNA
Brain

Keywords

  • Aging
  • Alzheimer
  • Amyloid
  • Brain
  • DNA-protein
  • Neuron
  • Promoter
  • Secretase
  • Transcription

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry
  • Genetics

Cite this

BACE1 gene promoter is differentially regulated : Detection of a novel promoter region for its cell type-specific regulation. / Lahiri, Debomoy; Maloney, Bryan; Ge, Yuan Wen.

In: Journal of Molecular Neuroscience, Vol. 28, No. 2, 2006, p. 193-210.

Research output: Contribution to journalArticle

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