Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

Fernanda G. De Felice, Diana Wu, Mary P. Lambert, Sara J. Fernandez, Pauline T. Velasco, Pascale N. Lacor, Eileen H. Bigio, Jasna Jerecic, Paul J. Acton, Paul J. Shughrue, Elizabeth Chen-Dodson, Gene G. Kinney, William L. Klein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

310 Scopus citations

Abstract

Alzheimer's disease (AD) is characterized by presence of extracellular fibrillar Aβ in amyloid plaques, intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated tau and elevated brain levels of soluble Aβ 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 Aβ oligomers from AD brains, but not by an extract from non-AD brains. Aβ 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.

Original languageEnglish (US)
Pages (from-to)1334-1347
Number of pages14
JournalNeurobiology of Aging
Volume29
Issue number9
DOIs
StatePublished - Sep 2008

Keywords

  • Alzheimer's disease
  • Aβ oligomers
  • Hippocampal neurons
  • PI3K
  • Src
  • Tau hyperphosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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