Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies
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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.
KeywordsAlzheimer’s disease Tau Synuclein TDP-43 Insulin resistance Insulin receptor substrate 1
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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