The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system

Am J Pathol. 2012 Oct;181(4):1426-35. doi: 10.1016/j.ajpath.2012.06.033. Epub 2012 Aug 4.


In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Biomarkers / metabolism
  • Centrifugation, Density Gradient
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Phosphorylation
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / pathology
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Transport
  • Synapses / metabolism*
  • Synapses / pathology
  • Synapses / ultrastructure
  • Ubiquitin / metabolism*
  • Ubiquitination
  • tau Proteins / chemistry
  • tau Proteins / metabolism*


  • Amyloid beta-Peptides
  • Biomarkers
  • Ubiquitin
  • tau Proteins
  • Proteasome Endopeptidase Complex