Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression

FASEB J. 2008 Nov;22(11):3823-35. doi: 10.1096/fj.08-109306. Epub 2008 Aug 14.

Abstract

Hyperhomocysteinemia (HHcy)-abnormally elevated plasma levels of homocysteine (Hcy)-has been associated with the development of neurodegenerative dementia and mild cognitive impairment. This association suggests that HHcy might facilitate memory loss in the elderly. As memory loss can occur through a deteriorated neurogenic capacity, we have studied the effects of Hcy on neural progenitor cells (NPCs) both in vitro and in vivo. We show that Hcy exerts an antiproliferative effect on basic fibroblast growth factor (bFGF) -stimulated NPCs isolated from the postnatal subventricular zone (SVZ), accompanied by inactivation of the extracellular signal-regulated kinase (Erk1/2) and inhibition of Erk1/2-dependent expression of cyclin E. Using a mice model we show that, under normal folate conditions, HHcy exerts an inhibitory effect on adult brain neurogenesis. This inhibition occurs in the caudal areas of the dentate gyrus (DG) of the hippocampus, a neurogenic area mainly involved in learning and memory performance, and in the SVZ, recently implicated in olfactory learning performance. In both areas reduced number of proliferative neuroblasts were found. Since neuroblasts are primarily bFGF-responsive progenitors already committed to a neuronal phenotype, our results strongly suggest that excess Hcy inhibits neurogenesis in the DG and SVZ by inhibiting the bFGF-dependent activation of Erk1/2 in these cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / metabolism*
  • Adult Stem Cells / pathology
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cognition Disorders / enzymology
  • Cognition Disorders / pathology
  • Cyclin E / biosynthesis*
  • Dementia / enzymology
  • Dementia / pathology
  • Dentate Gyrus / enzymology
  • Dentate Gyrus / pathology
  • Disease Models, Animal
  • Fibroblast Growth Factor 2 / metabolism*
  • Fibroblast Growth Factor 2 / pharmacology
  • Folic Acid / metabolism
  • Gene Expression Regulation / drug effects*
  • Homocysteine / metabolism
  • Homocysteine / pharmacology*
  • Humans
  • Hyperhomocysteinemia / enzymology
  • Hyperhomocysteinemia / pathology
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Neurodegenerative Diseases / enzymology
  • Neurodegenerative Diseases / pathology
  • Neurons / enzymology*
  • Trigeminal Caudal Nucleus / enzymology
  • Trigeminal Caudal Nucleus / pathology

Substances

  • Cyclin E
  • Homocysteine
  • Fibroblast Growth Factor 2
  • Folic Acid
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3