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The Journal of Neuroscience, January 1, 2002, 22(1):10-20
Rapid Tyrosine Phosphorylation of Neuronal Proteins Including
Tau and Focal Adhesion Kinase in Response to Amyloid-
Peptide Exposure: Involvement of Src Family Protein Kinases
Ritchie
Williamson1,
Timothy
Scales1,
Bruce R.
Clark1,
Graham
Gibb1,
C. Hugh
Reynolds1,
Stuart
Kellie3,
Ian N.
Bird3,
Ian M.
Varndell4,
Paul W.
Sheppard4,
Ian
Everall2, and
Brian H.
Anderton1
Department of 1 Neuroscience, 2 Section of
Experimental Neuropathology and Psychiatry, Institute of Psychiatry,
King's College London, London SE5 8AF, United Kingdom,
3 Yamanouchi Research Institute, Littlemore Park, Oxford
OX4 4SX, United Kingdom, and 4 Affiniti Research Products
Limited, Mamhead Castle, Mamhead, Exeter EX6 8HD, United Kingdom
The increased production of amyloid  -peptide (A) in
Alzheimer's disease is acknowledged to be a key pathogenic event. In this study, we examined the response of primary human and rat brain
cortical cultures to A administration and found a marked increase in
the tyrosine phosphorylation content of numerous neuronal proteins, including tau and putative microtubule-associated protein 2c
(MAP2c). We also found that paired helical filaments of
aggregated and hyperphosphorylated tau are tyrosine phosphorylated,
indicating that changes in the phosphotyrosine content of cytoplasmic
proteins in response to A are potentially an important process.
Increased tyrosine phosphorylation of cytoskeletal and other neuronal
proteins was specific to fibrillar A25-35 and
A1-42. The tyrosine phosphorylation was blocked by
addition of the Src family tyrosine kinase inhibitor
4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-D)pyramide (PP2) and the phosphatidylinositol 3-kinase inhibitor LY 294002. Tyrosine phosphorylation of tau and MAP2c was concomitant with an
increase in the tyrosine phosphorylation and subsequent putative activation of the non-receptor kinase, focal adhesion kinase (FAK). Immunoprecipitation of Fyn, a member of the Src family,
from A25-35-treated neurons showed an increased
association of Fyn with FAK. A treatment of cells also stimulated
the sustained activation of extracellular regulated kinase-2, which was
blocked by addition of PP2 and LY 294002, suggesting that
FAK/Fyn/PI3-kinase association is upstream of mitogen-activated protein
(MAP) kinase signaling in A-treated neurons. This cascade of
signaling events contains the earliest biochemical changes in neurons
to be described in response to A exposure and may be critical for
subsequent neurodegenerative changes.
Key words:
Alzheimer's disease; amyloid -peptide; cortical
neurons; tyrosine phosphorylation; FAK; Fyn; ERK2; tau; MAP2c
Copyright © 2002 Society for Neuroscience 0270-6474/02/22110-11$05.00/0
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