CIDeRGeneral Information:
| Id: | 457 |
| Diseases: |
Alzheimer disease
- [OMIM]
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| Mammalia | |
| review | |
| Reference: | de la Monte SM(2009) Insulin resistance and Alzheimers disease BMB Rep 42: 475-481 [PMID: 19712582] |
Interaction Information:
| Comment | AD is associated with progressive brain insulin resistance and insulin deficiency. Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease. |
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Formal Description Interaction-ID: 2014 |
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| Comment | Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease. |
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Formal Description Interaction-ID: 2015 |
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| Comment | Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease. |
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Formal Description Interaction-ID: 2017 |
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| Comment | Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease. |
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Formal Description Interaction-ID: 2018 |
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| Comment | Endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. |
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Formal Description Interaction-ID: 2022 |
affects_activity of disease |
| Comment | Another major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). |
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Formal Description Interaction-ID: 2023 |
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| Comment | Insulin and IGF (insulin-like growth factor) modulate neuronal growth, survival, differentiation, migration, metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, and plasticity. |
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Formal Description Interaction-ID: 2058 |
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| Comment | Insulin and IGF-I regulate growth, survival, and myelin production/maintenance in oligodendrocytes. |
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Formal Description Interaction-ID: 2060 |
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| Comment | Insulin and IGF (insulin-like growth factor) modulate neuronal growth, survival, differentiation, migration, metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, and plasticity. Impairments in ligand-receptor binding and downstream signaling through insulin/IGF/IRS pathways, together are sufficient to cause brain insuIin/IGF resistance in AD. |
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Formal Description Interaction-ID: 2061 |
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| Comment | Insulin and IGF-I regulate growth, survival, and myelin production/maintenance in oligodendrocytes. |
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Formal Description Interaction-ID: 2062 |
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| Drugbank entries | Show/Hide entries for IGF1 |
| Comment | In the early stages of AD, cerebral glucose utilization is reduced by as much as 45%, and blood flow by about 18%. In the later stages, metabolic and physiological abnormalities worsen, resulting in 55-65% reductions in cerebral blood flow. These observations suggest that AD-associated abnormalities in energy metabolism are caused by insulin resistance or reduced insulin actions in the brain, i.e. brain diabetes. |
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Formal Description Interaction-ID: 2063 |
disease decreases_activity of process glucose utilization |
| Comment | Genetic depletion of IRS-2 impairs neuronal proliferation and promotes intra-neuronal accumulation of phosphorylated tau and neurofibrillary tangles in the hippocampi of affected old mice. |
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Formal Description Interaction-ID: 2065 |
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| Comment | Genetic depletion of IRS-2 impairs neuronal proliferation, and promotes intra-neuronal accumulation of phosphorylated tau and neurofibrillary tangles in the hippocampi of affected old mice. |
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Formal Description Interaction-ID: 2067 |
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| Comment | Impairments in ligand-receptor binding and downstream signaling through insulin/IGF/IRS pathways, together are sufficient to cause brain insuIin/IGF resistance in AD. |
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Formal Description Interaction-ID: 2068 |
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| Comment | Inhibition of insulin/IGF-1 signaling blocks the Wnt pathway, which negatively regulates GSK-3beta via a PI3K/Akt-independent mechanism. In AD, both PI3K/Akt and Wnt signaling have been linked to key molecular abnormalities in AD. |
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Formal Description Interaction-ID: 2073 |
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| Comment | Inhibition of insulin/IGF-1 signaling blocks the Wnt pathway, which negatively regulates GSK-3beta via a PI3K/Akt-independent mechanism. In AD, both PI3K/Akt and Wnt signaling have been linked to key molecular abnormalities in AD. |
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Formal Description Interaction-ID: 2076 |
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| Drugbank entries | Show/Hide entries for GSK3B |
| Comment | GSK-3beta can be activated by oxidative stress, which is a consequence of insulin/IGF resistance and established feature of AD. |
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Formal Description Interaction-ID: 2078 |
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| Drugbank entries | Show/Hide entries for GSK3B |
| Comment | Hyper-phosphorylated tau cannot be transported into axons, and instead accumulates and aggregates in neuronal perikarya. |
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Formal Description Interaction-ID: 2079 |
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| Comment | Aberrant intra-neuronal phospho-tau accumulation contributes to neurodegeneration by enhancing oxidative stress, and triggering pathophysiological cascades that lead to increased apoptosis, mitochondrial dysfunction, and necrosis. |
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Formal Description Interaction-ID: 2080 |
protein modification MAPT-phos increases_activity of |
| Comment | Insulin influences Abeta peptide metabolism by accelerating its trafficking to the plasma membrane from the trans-Golgi network, where it's generated and increases extracellular levels of Abeta by promoting its secretion and inhibiting its degradation by insulin-degrading enzyme. |
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Formal Description Interaction-ID: 2081 |
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| Comment | Abeta can adversely affect insulin signaling by competing with and inhibiting insulin binding or reducing the affinity of insulin binding to its own receptor. |
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Formal Description Interaction-ID: 2082 |
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| Comment | Abeta accumulations can promote tau hyper-phosphorylation and formation of dementia associated paired helical filament-containing neuronal cytoskeletal lesions (neurofibrillary tangles, neuritic plaques, and neuropil threads) via functional impairment of the insulin signaling cascade, and attendant increased levels of GSK-3beta activity. |
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Formal Description Interaction-ID: 2083 |
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| Comment | Abeta accumulations can promote tau hyper-phosphorylation and formation of dementia associated paired helical filament-containing neuronal cytoskeletal lesions (neurofibrillary tangles, neuritic plaques, and neuropil threads) via functional impairment of the insulin signaling cascade, and attendant increased levels of GSK-3beta activity. |
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Formal Description Interaction-ID: 2084 |
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| Comment | Insulin degrading enzyme (IDE) can degrade soluble Abeta, and thereby regulate extracellular levels of Abeta. |
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Formal Description Interaction-ID: 2086 |
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| Drugbank entries | Show/Hide entries for IDE |
| Comment | In situ studies have demonstrated increased insulin degrading enzyme (IDE) immunoreactivity surrounding senile plaques, and reduced IDE expression in AD hippocampi. |
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Formal Description Interaction-ID: 2088 |
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| Drugbank entries | Show/Hide entries for IDE |
| Comment | In Alzheimer disease increased levels of Abeta are associated with reduced levels of CNS insulin and IGF-1. |
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Formal Description Interaction-ID: 2091 |
gene/protein affects_quantity of complex/PPI Insulin |
| Comment | Streptozotocin (STZ) is a nitrosamide methylnitrosourea linked to D-glucose, and taken up by insulin-producing cells such as beta cells in pancreatic islets. Once metabolized, the N-nitrosoureido is liberated and causes DNA damage and cell death through generation of reactive oxygen species. Intracerebroventricular (ic) injection of STZ impairs brain glucose utilization oxidative metabolism, insulin receptor function, and spatial learning and memory. ic-Streptozotocin treatments produced long-term and progressive deficits in learning, memory, cognition, behavior, and cerebral energy balance. Rat brains treated by ic-STZ had striking histopathological, biochemical, and molecular neurodegenerative abnormalities that overlapped with AD. |
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Formal Description Interaction-ID: 2114 |
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| Drugbank entries | Show/Hide entries for Streptozocin |
| Comment | Streptozotocin (STZ) is a nitrosamide methylnitrosourea linked to D-glucose, and taken up by insulin-producing cells such as beta cells in pancreatic islets. Once metabolized, the N-nitrosoureido is liberated and causes DNA damage and cell death through generation of reactive oxygen species. Intracerebroventricular (ic) injection of STZ impairs brain glucose utilization oxidative metabolism, insulin receptor function, and spatial learning and memory. ic-Streptozotocin treatments produced long-term and progressive deficits in learning, memory, cognition, behavior, and cerebral energy balance. Rat brains treated by ic-STZ had striking histopathological, biochemical, and molecular neurodegenerative abnormalities that overlapped with AD. |
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Formal Description Interaction-ID: 2117 |
drug/chemical compound increases_activity of phenotype |
| Drugbank entries | Show/Hide entries for Streptozocin |
| Comment | Streptozotocin (STZ) is a nitrosamide methylnitrosourea linked to D-glucose, and taken up by insulin-producing cells such as beta cells in pancreatic islets. Once metabolized, the N-nitrosoureido is liberated and causes DNA damage and cell death through generation of reactive oxygen species. Intracerebroventricular (ic) injection of STZ impairs brain glucose utilization oxidative metabolism, insulin receptor function, and spatial learning and memory. ic-Streptozotocin treatments produced long-term and progressive deficits in learning, memory, cognition, behavior, and cerebral energy balance. Rat brains treated by ic-STZ had striking histopathological, biochemical, and molecular neurodegenerative abnormalities that overlapped with AD. |
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Formal Description Interaction-ID: 2118 |
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| Drugbank entries | Show/Hide entries for Streptozocin |
| Comment | Intracerebroventricular streptozotocin (ic-STZ) increased expression of acetylcholinesterase in rat brains. |
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Formal Description Interaction-ID: 2179 |
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| Drugbank entries | Show/Hide entries for Streptozocin or ACHE |
| Comment | Intracerebroventricular streptozotocin (ic-STZ) increased expression of AbetaPP (amyloid beta precursor protein) in rat brains. |
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Formal Description Interaction-ID: 2181 |
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| Drugbank entries | Show/Hide entries for Streptozocin or APP |
| Comment | Intracerebroventricular streptozotocin (ic-STZ) decreased expression of choline acetyltransferase in rat brains. |
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Formal Description Interaction-ID: 2199 |
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| Drugbank entries | Show/Hide entries for Streptozocin |
| Comment | Insulin influences Abeta peptide metabolism by accelerating its trafficking to the plasma membrane from the trans-Golgi network, where it's generated and increases extracellular levels of Abeta by promoting its secretion and inhibiting its degradation by insulin-degrading enzyme. |
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Formal Description Interaction-ID: 12996 |
complex/PPI Insulin increases_transport of gene/protein |
| Comment | In Alzheimer disease increased levels of Abeta are associated with reduced levels of CNS insulin and IGF-1. |
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Formal Description Interaction-ID: 13021 |
phenotype increased Amyloid beta peptide level cooccurs with phenotype decreased IGF1 level |
| Comment | Hyper-phosphorylated tau cannot be transported into axons, and instead accumulates and aggregates in neuronal perikarya. |
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Formal Description Interaction-ID: 14595 |
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| Comment | Abeta accumulations can promote tau hyper-phosphorylation and formation of dementia associated paired helical filament-containing neuronal cytoskeletal lesions (neurofibrillary tangles, neuritic plaques, and neuropil threads) via functional impairment of the insulin signaling cascade, and attendant increased levels of GSK-3beta activity. |
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Formal Description Interaction-ID: 14606 |
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| Comment | Induction of apoptosis is one of the possible responses to oxidative stress. |
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Formal Description Interaction-ID: 36317 |
process increases_activity of |
| Comment | Abeta accumulations can promote tau hyper-phosphorylation and formation of dementia associated paired helical filament-containing neuronal cytoskeletal lesions (neurofibrillary tangles, neuritic plaques, and neuropil threads) via functional impairment of the insulin signaling cascade, and attendant increased levels of GSK-3beta activity. |
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Formal Description Interaction-ID: 50473 |
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| Comment | In Alzheimer disease increased levels of Abeta are associated with reduced levels of CNS insulin and IGF-1. |
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Formal Description Interaction-ID: 50503 |
phenotype increased Amyloid beta peptide level cooccurs with phenotype decreased insulin level |
| Comment | In situ studies have demonstrated increased insulin degrading enzyme (IDE) immunoreactivity surrounding senile plaques, and reduced IDE expression in AD hippocampi. |
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Formal Description Interaction-ID: 92511 |
disease increases_quantity of gene/protein |
| Drugbank entries | Show/Hide entries for IDE |