title: Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies.
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-pS(616), IRS1-pS(312) and downstream target Akt-pS(473) 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-pS(616) 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-pS(616) expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS(616) 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.
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA, mark.yarchoan@uphs.upenn.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Yarchoan
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.forename: Zoe
authors.initials: Z
authors.lastname: Arvanitakis
authors.forename: Hala
authors.initials: H
authors.lastname: Kazi
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Han
authors.forename: Natalia
authors.initials: N
authors.lastname: Louneva
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D012694:Serine / Q000378:metabolism*; D057177:TDP-43 Proteinopathies / Q000473:pathology; D024801:Tauopathies / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D055504:Insulin Receptor Substrate Proteins; D051844:alpha-Synuclein; D016875:tau Proteins; D012694:Serine
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