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

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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.

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Acknowledgments

We acknowledge the special contributions to case recruitment and evaluation of Christopher. M. Clark, Stephen J. DeArmond, Mark S. Forman, Murray Grossman, Howard I. Hurtig, Jason H. Karlawish and Leo F. McCluskey, Bruce L. Miller, and William Seeley, as well as neuropathology fellows and staff at the University of Pennsylvania. This work was supported by grants from the NIH P30 AG010124, P01 AG017586, AG039478, NS084965 and a gift from the Allen H. and Selma W. Berkman Charitable Trust.

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Authors and Affiliations

  1. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Mark Yarchoan

  2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Jon B. Toledo, Edward B. Lee, Virginia M.-Y. Lee & John Q. Trojanowski

  3. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Hala Kazi, Li-Ying Han, Natalia Louneva, Sangwon F. Kim & Steven E. Arnold

  4. Departments of Psychiatry and Neurology, Penn Memory Center, Perelman School of Medicine, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA, 19104, USA

    Steven E. Arnold

  5. Rush Alzheimer’s Disease Center, Rush University, Chicago, IL, 60612, USA

    Zoe Arvanitakis

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  1. Mark Yarchoan
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401_2014_1328_MOESM1_ESM.tif

Supplementary material 1 (TIFF 4070 kb) SUPPLEMENTAL FIGURE 1A: IRS1-pS312 pathology percent area measures in midfrontal cortex in AD, tauopathies (including Pick’s disease, corticobasal degeneration and progressive supranuclear palsy), and normal aging. As compared to the normal aging group, IRS1-pS312 measures are markedly increased in AD but were also significantly elevated in other tauopathies. Error bars represent standard error of the mean

401_2014_1328_MOESM2_ESM.tif

Supplementary material 2 (TIFF 4067 kb) SUPPLEMENTAL FIGURE 1B: ELISA measurement of IRS1-pS312 expression in midfrontal gyrus cortex from AD, tauopathies (including Pick’s disease, corticobasal degeneration and progressive supranuclear palsy), and normal aging

401_2014_1328_MOESM3_ESM.tif

Supplementary material 3 (TIFF 757 kb) SUPPLEMENTAL FIGURE 1C: Serine phosphorylation of Akt (Akt-pS473) percent area measures in midfrontal cortex in AD, tauopathies, and normal aging. Error bars represent standard error of the mean

401_2014_1328_MOESM4_ESM.tif

Supplementary material 4 (TIFF 1901 kb) SUPPLEMENTAL FIGURE 2A. Cell-type specificity of pathological IRS1 expression in CA1 subfield of hippocampus in Alzheimer’s disease. a-c) Double immunofluorescence labeling with antibodies to IRS1-pS616 (a,c) and the neuron-specific microtubule-associated protein 2 (MAP2) (b,c). Pathological IRS1 was observed in some MAP2-immunoreactive neurons perikarya (examples indicated with vertical white arrowheads) as well as in other cell nuclei. d-f) Double labeling for IRS1-pS616 (d,f) and glial fibrillary acidic protein (GFAP) (e,f), a marker of astrocytes. GFAP- astrocytes (examples indicated with horizontal white arrows) (d-f) were seen to exhibit IRS1 in nuclei while pathological IRS1was observed only in non-astrocytes (neurons, vertical white arrowheads). g-i) Double labeling for IRS1-pS616 (g,i) and CD68 antigen (h,i), a marker of microglia (g,i). No co-localizations were observed. Examples of pathological iRS1-pS616 are indicated with vertical white arrowheads (g,i)

401_2014_1328_MOESM5_ESM.tif

Supplementary material 5 (TIFF 899 kb) SUPPLEMENTAL FIGURE 2B: IRS1-pS616 and GFAP double labeling in CA1 subfield of hippocampus corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Both CBD (a-c) and PSP (d-f) showed abnormal IRS1 (arrowheads) in cells that did not co-localize with GFAP

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Yarchoan, M., Toledo, J.B., Lee, E.B. et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol 128, 679–689 (2014). https://doi.org/10.1007/s00401-014-1328-5

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