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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 β‐APP production and develop cortical amyloid plaques at an early age. As β‐APP and Notch are both processed by γ‐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 β‐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 γ‐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.—Activation of the Notch pathway in Down syndrome: cross‐talk of Notch and APP. Fischer D. F., Van Dijk R., Sluijs J. A., Nair S. M., Racchi M., Levelt C. N., Van Leeuwen F. W., Hol E. M. Activation of the Notch pathway in Down syndrome: cross‐talk of Notch and APP. FASEB J. 19, 1451–1458 (2005)