Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP.
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.
Fischer
David F
DF
Netherlands Institute for Brain Research, Amsterdam, The Netherlands. david@cncr.vu.nl
van Dijk
Renske
R
Sluijs
Jacqueline A
JA
Nair
Suresh M
SM
Racchi
Marco
M
Levelt
Christiaan N
CN
van Leeuwen
Fred W
FW
Hol
Elly M
EM
D000328:Adult; D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D004314:Down Syndrome / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000072056:Transcription Factor HES-1; D015533:Transcriptional Activation
D016564:Amyloid beta-Protein Precursor; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C091042:APBB1 protein, human; C078493:HES1 protein, human