Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers.
Alzheimer's disease (AD) is characterized by presence of extracellular fibrillar A beta in amyloid plaques, intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated tau and elevated brain levels of soluble A beta oligomers (ADDLs). A major question is how these disparate facets of AD pathology are mechanistically related. Here we show that, independent of the presence of fibrils, ADDLs stimulate tau phosphorylation in mature cultures of hippocampal neurons and in neuroblastoma cells at epitopes characteristically hyperphosphorylated in AD. A monoclonal antibody that targets ADDLs blocked their attachment to synaptic binding sites and prevented tau hyperphosphorylation. Tau phosphorylation was blocked by the Src family tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-D)pyramide (PP1), and by the phosphatidylinositol-3-kinase inhibitor LY294002. Significantly, tau hyperphosphorylation was also induced by a soluble aqueous extract containing A beta oligomers from AD brains, but not by an extract from non-AD brains. A beta oligomers have been increasingly implicated as the main neurotoxins in AD, and the current results provide a unifying mechanism in which oligomer activity is directly linked to tau hyperphosphorylation in AD pathology.
De Felice
Fernanda G
FG
Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA.
Wu
Diana
D
Lambert
Mary P
MP
Fernandez
Sara J
SJ
Velasco
Pauline T
PT
Lacor
Pascale N
PN
Bigio
Eileen H
EH
Jerecic
Jasna
J
Acton
Paul J
PJ
Shughrue
Paul J
PJ
Chen-Dodson
Elizabeth
E
Kinney
Gene G
GG
Klein
William L
WL
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016875:tau Proteins