Steady-state increase of cAMP-response element binding protein, Rac, and PAK signaling in presenilin-deficient neurons

J Neurochem. 2008 Mar;104(6):1637-48. doi: 10.1111/j.1471-4159.2007.05102.x. Epub 2007 Nov 7.


Mutations in the genes encoding presenilins (PS1 and PS2) account for the majority of cases of early-onset Alzheimer's disease. PS1 and PS2 form the catalytic center of gamma-secretase, an enzyme responsible for intramembraneous proteolysis of several type I transmembrane proteins. Many gamma-secretase substrates are coupled to intracellular signaling events such as cAMP-response element binding protein and Rac1/p21-activated kinase pathways, which are associated with synaptic function. Here, we have examined the activation of these pathways in neurons lacking PS1 expression or gamma-secretase activity. We found evidence for heightened steady-state activation of cAMP-response element binding protein, Rac1, and p21-activated kinase signaling in PS-deficient neurons. Our study highlights the importance of PS-dependent proteolytic cleavage of gamma-secretase substrates in regulating neuronal signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / metabolism*
  • Neuropeptides / metabolism*
  • Presenilin-1 / genetics*
  • Presenilin-1 / metabolism
  • Signal Transduction / physiology
  • p21-Activated Kinases / metabolism*
  • rac GTP-Binding Proteins / metabolism*
  • rac1 GTP-Binding Protein


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Neuropeptides
  • Presenilin-1
  • Rac1 protein, mouse
  • p21-Activated Kinases
  • Amyloid Precursor Protein Secretases
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein