Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies

Mark Yarchoan, Jon B. Toledo, Edward B. Lee, Zoe Arvanitakis, Hala Kazi, Li Ying Han, Natalia Louneva, Virginia M.Y. Lee, Sangwon F. Kim, John Q. Trojanowski, Steven E. Arnold

Research output: Contribution to journalArticle

Abstract

Neuronal insulin signaling abnormalities have been associated with Alzheimer’s disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS616, IRS1-pS312 and downstream target Akt-pS473 measures were most elevated in AD but were also significantly increased in the tauopathies: Pick’s disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS616 with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS616 expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS616 frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-β.

Original languageEnglish (US)
Pages (from-to)679-689
Number of pages11
JournalActa neuropathologica
Volume128
Issue number5
DOIs
StatePublished - Jan 1 2014

Keywords

  • Alzheimer’s disease
  • Insulin receptor substrate 1
  • Insulin resistance
  • Synuclein
  • TDP-43
  • Tau

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Yarchoan, M., Toledo, J. B., Lee, E. B., Arvanitakis, Z., Kazi, H., Han, L. Y., Louneva, N., Lee, V. M. Y., Kim, S. F., Trojanowski, J. Q., & Arnold, S. E. (2014). Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta neuropathologica, 128(5), 679-689. https://doi.org/10.1007/s00401-014-1328-5