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PD98059 Prevents Neurite Degeneration Induced by Fibrillar β‐Amyloid in Mature Hippocampal Neurons
Author(s) -
Rapoport Mark,
Ferreira Adriana
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0740125.x
Subject(s) - neurite , senile plaques , mapk/erk pathway , phosphorylation , signal transduction , hippocampal formation , microbiology and biotechnology , neuroscience , kinase , protein kinase a , biology , chemistry , alzheimer's disease , pathology , biochemistry , medicine , disease , in vitro
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 Ser 199 /Ser 202 ) 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.