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O3–02–02: Expression of pIRS–1 (S312 and S616) is elevated in MCI and AD and correlates with cognitive impairment and neurofibrillary pathology
Author(s) -
Talbot Konrad,
Han LiYing,
Schneider Julie A.,
Wilson Robert S.,
Bennett David A.,
Arnold Steven E.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.197
Subject(s) - insulin resistance , insulin receptor , medicine , diabetes mellitus , hippocampal formation , endocrinology , hippocampus , cognitive decline , biology , disease , neuroscience , pathology , dementia
tion of pro-death signaling. Recent studies of human postmortem brains linked the molecular and pathological lesions in AD to major impairments in: 1) insulin and insulin-like growth factor (IGF) gene expression; 2) expression and function of the insulin and IGF receptors; 3) neuronal survival signaling; and 4) acetylcholine homeostasis, and showed each of these abnormalities increases with progression of AD. The co-existence of insulin/IGF deficiency and insulin/IGF resistance suggests that AD represents a brain-specific form of diabetes, i.e. Type 3 diabetes. We generated an experimental animal model in which intracerebral Streptozotocin (icSTZ) was used to deplete brain and not pancreatic insulin/IGF, and produce neurodegeneration that is similar to human AD. The ic-STZ-injected rats did not have hyperglycemia, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration with cell loss, gliosis, and increased immunoreactivity for p53, activated glycogen synthase kinase 3 , phospho-tau, ubiquitin, and amyloid. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated with reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. Further studies showed that treatment with peroxisome-proliferator activated receptor agonists effectively prevented the ic-STZ-induced Type 3 diabetes and preserved learning and memory. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes. The results also suggest that early treatment with insulin sensitizer agent may prevent or reduce the severity of AD.