PD98059 prevents neurite degeneration induced by fibrillar β-amyloid in mature hippocampal neurons

Mark Rapoport, Adriana Ferreira*

*Corresponding author for this work

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

How senile plaques and neurofibrillary tangles are linked represents a major gap in our understanding of the pathophysiology of Alzheimer's disease (AD). We have previously shown that the addition of fibrillar β-amyloid (Aβ) to mature hippocampal neurons results in progressive neuritic degeneration accompanied by the enhanced phosphorylation of adult tau isoforms. In the present study, we sought to obtain more direct evidence of the signal transduction pathway(s) activated by fibrillar Aβ leading to tau phosphorylation and the generation of dystrophic neurites. Our results indicated that fibrillar Aβ induced the progressive and sustained activation of the mitogen-activated protein kinase (MAPK) in mature hippocampal neurons. On the other hand, the specific inhibition of the MAPK signal transduction pathway by means of PD98059, a MAPK kinase (MEK) specific inhibitor, prevented the phosphorylation of tau (at Ser199/Ser202) induced by fibrillar Aβ. In addition, the inhibition of MAPK activation partially prevented neurite degeneration. Taken-collectively, our results suggest that the sustained activation of the MAPK signal transduction pathway induced by fibrillar Aβ may lead to the abnormal phosphorylation of tau and the neuritic degeneration observed in AD.

Original languageEnglish (US)
Pages (from-to)125-133
Number of pages9
JournalJournal of neurochemistry
Volume74
Issue number1
DOIs
StatePublished - Jan 10 2000

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Keywords

  • Fibrillar β-amyloid
  • MEK1 inhibitor
  • Mitogen-activated protein kinase signal transduction pathway
  • Neurite degeneration
  • Tau phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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