Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: Implications for cellular Aβ metabolism

LEAL MC; SURACE EI; HOLGADO MP; FERRARI CC; TARELLI R; PITOSSI F; WISNIEWSKI T; CASTAÑO EM; MORELLI L

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2011 vol. 1823 p. 227 - 235

0167-4889

Cerebral amyloid β (Aβ) accumulation is pathogenically associated with sporadic Alzheimer´s disease (SAD).BACE-1 is involved in Aβ generation while insulin-degrading enzyme (IDE) partakes in Aβ proteolytic clearance.Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while theopposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstratean increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampusof 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 Aβ accumulation. Also, NICD, HES-1 andHey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functionalsites 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 wereverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsiblefor the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligandJAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a NotchdependentIDE transcriptional modulation may impact on Aβ metabolism providing a functional link betweenNotch signaling and the amyloidogenic pathway in SAD