Tau Is Hyperphosphorylated in the Insulin-Like Growth Factor-I Null Brain

Abstract

IGF action has been implicated in the promotion of oxidative stress and aging in invertebrate and murine models. However, some in vitro models suggest that IGF-I specifically prevents neuronal oxidative damage. To investigate whether IGF-I promotes or retards brain aging, we evaluated signs of oxidative stress and neuropathological aging in brains from 400-d-old Igf1−/− and wild-type (WT) mice. Lipofuscin pigment accumulation reflects oxidative stress and aging, but we found no difference in lipofuscin deposition in Igf1−/− and WT brains. Likewise, there was no apparent difference in accumulation of nitrotyrosine residues in Igf1−/− and WT brains, except for layer IV/V of the cerebral cortex, where these proteins were about 20% higher in the Igf1−/− brain (P = 0.03). We found no difference in the levels of oxidative stress-related enzymes, neuronal nitric oxide synthase, inducible nitric oxide synthase, and superoxide dismutase in Igf1−/− and WT brains. Tau is a microtubule-associated protein that causes the formation of neurofibrillary tangles and senile plaques as it becomes hyperphosphorylated in the aging brain. Tau phosphorylation was dramatically increased on two specific residues, Ser-396 and Ser-202, both glycogen synthase kinases target sites implicated in neurodegeneration. These observations indicate that IGF-I has a major role in regulating tau phosphorylation in the aging brain, whereas its role in promoting or preventing oxidative stress remains uncertain.