Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP

David F Fischer, Renske van Dijk, Jacqueline A Sluijs, Suresh M Nair, Marco Racchi, Christiaan N Levelt, Fred W van Leeuwen, Elly M Hol

Research output: Contribution to journalArticleAcademicpeer-review


Down syndrome (DS) patients suffer from mental retardation, but also display enhanced beta-APP production and develop cortical amyloid plaques at an early age. As beta-APP and Notch are both processed by gamma-secretase, we analyzed expression of the Notch signaling pathway in the adult DS brain and in a model system for DS, human trisomy 21 fibroblasts by quantitative PCR. In adult DS cortex we found that Notch1, Dll1 and Hes1 expression is up-regulated. Moreover, DS fibroblasts and Alzheimer disease cortex also show overexpression of Notch1 and Dll1, indicating that enhanced beta-APP processing found in both DS and AD could be instrumental in these changes. Using pull-down studies we could demonstrate interaction of APP with Notch1, suggesting that these transmembrane proteins form heterodimers, but independent of gamma-secretase. We could demonstrate binding of the intracellular domain of Notch1 to the APP adaptor protein Fe65. Furthermore, activated Notch1 can trans-activate an APP target gene, Kai1, and vice versa, activated APP can trans-activate the classical Notch target gene Hes1. These data suggest that Notch expression is activated in Down syndrome, possibly through cross-talk with APP signaling. This interaction might affect brain development, since the Notch pathway plays a pivotal role in neuron-glia differentiation.

Original languageEnglish
Pages (from-to)1451-8
Number of pages8
JournalFASEB Journal
Issue number11
Publication statusPublished - Sept 2005


  • Adult
  • Aged
  • Amyloid beta-Protein Precursor
  • Basic Helix-Loop-Helix Transcription Factors
  • Cells, Cultured
  • Cerebral Cortex
  • Down Syndrome
  • Homeodomain Proteins
  • Humans
  • Middle Aged
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Receptors, Notch
  • Signal Transduction
  • Transcription Factor HES-1
  • Transcriptional Activation
  • Journal Article
  • Research Support, Non-U.S. Gov't


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