Tau is hyperphosphorylated in the insulin-like growth factor-I null brain.
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.
Cheng
Clara M
CM
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA. chengc@mail.nih.gov
Tseng
Victor
V
Wang
Jie
J
Wang
Daniel
D
Matyakhina
Ludmila
L
Bondy
Carolyn A
CA
D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D004350:Drug Residues / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000172:deficiency*; D008062:Lipofuscin / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D018384:Oxidative Stress; D010766:Phosphorylation; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D008062:Lipofuscin; D016875:tau Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D019001:Nitric Oxide Synthase