Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1823, Issue 2, Pages 227-235Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2011.09.014
Keywords
Amyloid beta metabolism; Notch signaling; HES; Hey; Transcriptional repressors; IDE gene promoter
Categories
Funding
- Agencia Nacional de Promocion Cientifica y Technologica (ANPCyT) [PICT38009, PICT 2354]
- Consejo Nacional de Investigaciones Cientificas y Technologicas (CONICET) [PIP6168, PIP693, PIP1660]
- PHS [R24-MH 068855]
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Cerebral amyloid beta (A beta) accumulation is pathogenically associated with sporadic Alzheimer's disease (SAD). BACE-1 is involved in A beta generation while insulin-degrading enzyme (IDE) partakes in A beta proteolytic clearance. Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while the opposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstrate an increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampus of SAD brains as compared to controls. Transient transfection of Notch intracellular domain (NICD) in N2aSW cells, mouse neuroblastoma cells (N2a) stably expressing human amyloid precursor protein (APP) Swedish mutation, reduce IDE mRNA levels, promoting extracellular A beta accumulation. Also, NICD, HES-1 and Hey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functional sites located at -379/-372 and -310-303 from the first translation start site in the -575/-19 (556 bp) fragment of IDE proximal promoter. By site-directed mutagenesis of the IDE promoter region we reverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsible for the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1 and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a Notch-dependent IDE transcriptional modulation may impact on A beta metabolism providing a functional link between Notch signaling and the amyloidogenic pathway in SAD. (C) 2011 Elsevier B.V. All rights reserved.
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