Journal
NEUROBIOLOGY OF AGING
Volume 29, Issue 9, Pages 1334-1347Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.02.029
Keywords
Alzheimer's disease; A beta oligomers; tau hyperphosphorylation; hippocampal neurons; Src; PI3K
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Funding
- NIA NIH HHS [R01 AG018877-03, R01-AG11385, R01 AG022547, P30 AG013854-139003, R01 AG018877, R01-AG18877, R01 AG011385, R01 AG029460-01, P30 AG013854, R01 AG022547-03, R01 AG011385-06, R01-AG22547, R01 AG029460] Funding Source: Medline
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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 (PPI), 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. (c) 2007 Elsevier Inc. All rights reserved.
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