Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers
| Autor: | Paul Acton, Sara J. Fernandez, Gene G. Kinney, Diana Wu, William L. Klein, Mary P. Lambert, Elizabeth Chen-Dodson, Paul J. Shughrue, Eileen H. Bigio, Jasna Jerecic, Fernanda G. De Felice, Pauline T. Velasco, Pascale N. Lacor |
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| Rok vydání: | 2008 |
| Předmět: |
Aging
Hippocampus tau Proteins Hippocampal formation SRC Family Tyrosine Kinase Article chemistry.chemical_compound Alzheimer Disease medicine Extracellular Humans LY294002 Phosphorylation Cells Cultured Neurons Amyloid beta-Peptides General Neuroscience medicine.disease Peptide Fragments Cell biology chemistry Biochemistry Neurology (clinical) Geriatrics and Gerontology Alzheimer's disease Developmental Biology Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Neurobiology of Aging. 29:1334-1347 |
| ISSN: | 0197-4580 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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