General Information:

Id: 457
Diseases: Alzheimer disease - [OMIM]
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.
Formal Description
Interaction-ID: 2014

phenotype

insulin resistance

increases_activity of

in brain
Comment Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease.
Formal Description
Interaction-ID: 2015

increases_activity of

Comment Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease.
Formal Description
Interaction-ID: 2017

phenotype

insulin resistance

increases_activity of

phenotype

neurodegeneration

Comment Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease.
Formal Description
Interaction-ID: 2018

increases_activity of

phenotype

neurodegeneration

Comment Endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities.
Formal Description
Interaction-ID: 2022
Comment Another major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM).
Formal Description
Interaction-ID: 2023

disease

Obesity

increases_activity of

phenotype

cognitive impairment

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.
Formal Description
Interaction-ID: 2058

complex/PPI

Insulin

affects_activity of

process

neurogenesis

Comment Insulin and IGF-I regulate growth, survival, and myelin production/maintenance in oligodendrocytes.
Formal Description
Interaction-ID: 2060

complex/PPI

Insulin

affects_activity of

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.
Formal Description
Interaction-ID: 2061

gene/protein

IGF

affects_activity of

process

neurogenesis

Comment Insulin and IGF-I regulate growth, survival, and myelin production/maintenance in oligodendrocytes.
Formal Description
Interaction-ID: 2062

gene/protein

IGF1

affects_activity of

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.
Formal Description
Interaction-ID: 2063

decreases_activity of

process

glucose utilization

it is suggested that AD-associated abnormalities in energy metabolism are caused by insulin resistance or reduced insulin actions in the brain, i.e. brain diabetes
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.
Formal Description
Interaction-ID: 2065

gene/protein

IRS2

affects_quantity of

protein modification

MAPT-phos

in hippocampus
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.
Formal Description
Interaction-ID: 2067

gene/protein

IRS2

affects_quantity of

in hippocampus
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.
Formal Description
Interaction-ID: 2068

affects_activity of

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.
Formal Description
Interaction-ID: 2073

affects_activity of

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.
Formal Description
Interaction-ID: 2076

affects_activity of

gene/protein

GSK3B

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.
Formal Description
Interaction-ID: 2078

increases_activity of

gene/protein

GSK3B

Drugbank entries Show/Hide entries for GSK3B
Comment Hyper-phosphorylated tau cannot be transported into axons, and instead accumulates and aggregates in neuronal perikarya.
Formal Description
Interaction-ID: 2079

protein modification

MAPT-hyperphos

NOT is localized in

cellular component

axon

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.
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.
Formal Description
Interaction-ID: 2081

complex/PPI

Insulin

affects_activity of

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.
Formal Description
Interaction-ID: 2082

gene/protein

Amyloid beta peptide

affects_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.
Formal Description
Interaction-ID: 2083

gene/protein

Amyloid beta peptide

increases_quantity of

protein modification

MAPT-hyperphos

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.
Formal Description
Interaction-ID: 2084

gene/protein

Amyloid beta peptide

increases_activity of

phenotype

neuronal cytoskeletal lesion

Comment Insulin degrading enzyme (IDE) can degrade soluble Abeta, and thereby regulate extracellular levels of Abeta.
Formal Description
Interaction-ID: 2086

gene/protein

IDE

decreases_quantity of

complex/PPI

Amyloid beta peptide (soluble)

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.
Formal Description
Interaction-ID: 2088

decreases_expression of

gene/protein

IDE

in hippocampus
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.
Formal Description
Interaction-ID: 2091

gene/protein

Amyloid beta peptide

affects_quantity of

complex/PPI

Insulin

in CNS; if levels of APP / Amyloid beta peptide in AD are increased then level of insulin is reduced
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.
Formal Description
Interaction-ID: 2114

drug/chemical compound

Streptozocin

decreases_activity of

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.
Formal Description
Interaction-ID: 2117

drug/chemical compound

Streptozocin

increases_activity of

in brain
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.
Formal Description
Interaction-ID: 2118

drug/chemical compound

Streptozocin

increases_activity of

phenotype

neurodegeneration

Drugbank entries Show/Hide entries for Streptozocin
Comment Intracerebroventricular streptozotocin (ic-STZ) increased expression of acetylcholinesterase in rat brains.
Formal Description
Interaction-ID: 2179

drug/chemical compound

Streptozocin

increases_expression of

gene/protein

ACHE

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.
Formal Description
Interaction-ID: 2181

drug/chemical compound

Streptozocin

increases_expression of

gene/protein

APP

Drugbank entries Show/Hide entries for Streptozocin or APP
Comment Intracerebroventricular streptozotocin (ic-STZ) decreased expression of choline acetyltransferase in rat brains.
Formal Description
Interaction-ID: 2199

drug/chemical compound

Streptozocin

decreases_expression of

gene/protein

CHAT

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.
Formal Description
Interaction-ID: 12996

complex/PPI

Insulin

increases_transport of

gene/protein

Amyloid beta peptide

from the trans-Golgi-network to the plasma membrane
Comment In Alzheimer disease increased levels of Abeta are associated with reduced levels of CNS insulin and IGF-1.
Formal Description
Interaction-ID: 13021

phenotype

increased Amyloid beta peptide level

cooccurs with

phenotype

decreased IGF1 level

in CNS; in AD
Comment Hyper-phosphorylated tau cannot be transported into axons, and instead accumulates and aggregates in neuronal perikarya.
Formal Description
Interaction-ID: 14595

protein modification

MAPT-hyperphos

is localized in

cellular component

perikaryon

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.
Formal Description
Interaction-ID: 14606

gene/protein

Amyloid beta peptide

increases_quantity of

protein modification

MAPT-hyperphos

Comment Induction of apoptosis is one of the possible responses to oxidative stress.
Formal Description
Interaction-ID: 36317
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.
Formal Description
Interaction-ID: 50473

phenotype

neuronal cytoskeletal lesion

increases_activity of

Comment In Alzheimer disease increased levels of Abeta are associated with reduced levels of CNS insulin and IGF-1.
Formal Description
Interaction-ID: 50503

phenotype

increased Amyloid beta peptide level

cooccurs with

phenotype

decreased insulin level

in CNS; in AD
Comment In situ studies have demonstrated increased insulin degrading enzyme (IDE) immunoreactivity surrounding senile plaques, and reduced IDE expression in AD hippocampi.
Formal Description
Interaction-ID: 92511

increases_quantity of

gene/protein

IDE

surrounding senile plaques in AD hippocampi
Drugbank entries Show/Hide entries for IDE