CIDeRplusGeneral Information:
| Id: | 3,699 |
| Diseases: |
Alzheimer disease
- [OMIM]
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| Mammalia | |
| review | |
| Reference: | Cai H et al.(2012) Metabolic dysfunction in Alzheimers disease and related neurodegenerative disorders Curr Alzheimer Res 9: 5-17 [PMID: 22329649] |
Interaction Information:
| Comment | Uncontrolled, progressive weight loss and abnormal glucose tolerance are common metabolic dysfunctions observed in AD (Alzheimer disease), HD (Huntington disease), and PD (Parkinson disease). |
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Formal Description Interaction-ID: 35731 |
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| Comment | The disease loci of AD (Alzheimer disease), HD (Huntington disease), and PD (Parkinson disease) often involve the hypothalamus, a key regulatory brain region for global energy homeostasis. |
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Formal Description Interaction-ID: 35740 |
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| Comment | The disease loci of AD (Alzheimer disease), HD (Huntington disease), and PD (Parkinson disease) often involve the hypothalamus, a key regulatory brain region for global energy homeostasis. |
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Formal Description Interaction-ID: 35749 |
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| Comment | Excess body weight during middle-age is linked to an increased risk of developing AD. Obesity (Body Mass Index - BMI greater than 30) at 40-45 years of age is associated with a 3-fold increase in the risk of developing AD, while being overweight (BMI between 25 and 30) is associated with a 2-fold increase in AD risk, compared to individuals with a normal BMI. |
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Formal Description Interaction-ID: 35802 |
phenotype increases_activity of disease |
| Comment | Rats fed a high-fat/glucose diet, to induce insulin resistance, were found to exhibit impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation in the CA1 region. |
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Formal Description Interaction-ID: 35831 |
phenotype affects_activity of phenotype |
| Comment | Reducing caloric intake increases healthspan, reduces damage in the brain due to aging, and provides greater maintenance of various brain functions, potentially through hormetic mechanisms. |
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Formal Description Interaction-ID: 35832 |
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| Comment | The Rotterdam study revealed an approximate two-fold increase in risk of developing AD in patients with diabetes (DM), compared to patients without the condition and DM requiring insulin treatment was associated with a four-fold increase in incidence of AD. |
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Formal Description Interaction-ID: 35833 |
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| Comment | Rats fed a high-fat/glucose diet, to induce insulin resistance, were found to exhibit impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation in the CA1 region. |
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Formal Description Interaction-ID: 35834 |
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| Comment | Rats fed a high-fat/glucose diet, to induce insulin resistance, were found to exhibit impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation in the CA1 region. |
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Formal Description Interaction-ID: 35835 |
phenotype increases_activity of phenotype reduced hippocampal dendritic spine density |
| Comment | Rats fed a high-fat/glucose diet, to induce insulin resistance, were found to exhibit impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation in the CA1 region. |
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Formal Description Interaction-ID: 35836 |
phenotype increases_activity of phenotype reduced long-term potentiation |
| Comment | Reducing caloric intake increases healthspan, reduces damage in the brain due to aging, and provides greater maintenance of various brain functions, potentially through hormetic mechanisms. |
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Formal Description Interaction-ID: 35837 |
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| Comment | The presence of type 2 DM and the ApoE4 allele together has also been shown to increase the risk of developing AD, to more than five-fold, compared to individuals without those two conditions. |
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Formal Description Interaction-ID: 35842 |
gene/protein mutant increases_activity of disease |
| Comment | Hyperinsulinemia is associated with a doubled risk of developing AD. |
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Formal Description Interaction-ID: 35849 |
phenotype increases_activity of disease |
| Comment | Abnormal glucose homeostasis is linked to cognitive dysfunction in such that patients with either type 1 or type 2 DM display significant memory impairment and attention deficits on cognitive testing compared to control subjects. |
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Formal Description Interaction-ID: 35855 |
phenotype increases_activity of phenotype cognitive impairment |
| Comment | Hyperglycemia can lead to the activation of the polyol pathway, formation of advanced glycation end products, and activation of protein kinase C. |
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Formal Description Interaction-ID: 35887 |
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| Comment | Hyperglycemia can lead to the activation of the polyol pathway, formation of advanced glycation end products, and activation of protein kinase C. |
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Formal Description Interaction-ID: 35888 |
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| Comment | Hyperglycemia can lead to the activation of the polyol pathway, formation of advanced glycation end products, and activation of protein kinase C. |
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Formal Description Interaction-ID: 35890 |
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| Comment | Administration of high amounts of glucose can induce tau cleavage and apoptosis. |
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Formal Description Interaction-ID: 35891 |
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| Comment | Administration of high amounts of glucose can induce tau cleavage and apoptosis. |
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Formal Description Interaction-ID: 35892 |
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| Comment | There is a higher density of insulin receptors in the brain of AD patients compared to control subjects. |
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Formal Description Interaction-ID: 35893 |
disease increases_quantity of complex/PPI Insulin receptor |
| Comment | Hyperinsulinemia (a marker of insulin resistance in the metabolic disease spectrum) can decrease the availability of insulin degrading enzyme (IDE), which is essential for the degradation and clearance of Abeta in the brain. |
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Formal Description Interaction-ID: 35895 |
phenotype decreases_quantity of gene/protein |
| Drugbank entries | Show/Hide entries for IDE |
| Comment | Mouse models of type 1 and type 2 DM are associated with increased tau phosphorylation, which is likely secondary to glucotoxicity. |
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Formal Description Interaction-ID: 35904 |
disease cooccurs with phenotype increased MAPT-phos level |
| Comment | Mouse models of type 1 and type 2 DM are associated with increased tau phosphorylation, which is likely secondary to glucotoxicity. |
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Formal Description Interaction-ID: 35908 |
disease cooccurs with phenotype increased MAPT-phos level |
| Comment | PPARG activation suppresses the expression of inflammatory genes, which, clinically, has been shown to ameliorate neurodegeneration. |
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Formal Description Interaction-ID: 35927 |
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| Drugbank entries | Show/Hide entries for PPARG |
| Comment | PPARG activation suppresses the expression of inflammatory genes, which, clinically, has been shown to ameliorate neurodegeneration. |
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Formal Description Interaction-ID: 35928 |
gene/protein decreases_activity of phenotype |
| Drugbank entries | Show/Hide entries for PPARG |
| Comment | Treatment with a PPARG agonist reduces disease-related pathology, improves learning and memory, and enhances attention in AD patients. |
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Formal Description Interaction-ID: 35949 |
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| Comment | Treatment with a PPARG agonist reduces disease-related pathology, improves learning and memory, and enhances attention in AD patients. |
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Formal Description Interaction-ID: 35950 |
drug/chemical compound PPARG agonist increases_activity of process |
| Comment | Treatment with a PPARG agonist reduces disease-related pathology, improves learning and memory, and enhances attention in AD patients. |
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Formal Description Interaction-ID: 35951 |
drug/chemical compound PPARG agonist increases_activity of process attention |
| Comment | The cyclooxygenase inhibitor Ibuprofen (iso-butyl-propanoic-phenolic acid), which can activate PPARG, has been demonstrated to significantly reduce amyloid pathology and reduce microglial-mediated inflammation in a mouse model of AD, potentially via PPARG signaling. |
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Formal Description Interaction-ID: 35952 |
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| Drugbank entries | Show/Hide entries for Ibuprofen or PPARG |
| Comment | The cyclooxygenase inhibitor Ibuprofen (iso-butyl-propanoic-phenolic acid), which can activate PPARG, has been demonstrated to significantly reduce amyloid pathology and reduce microglial-mediated inflammation in a mouse model of AD, potentially via PPARG signaling. |
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Formal Description Interaction-ID: 35954 |
drug/chemical compound decreases_activity of process |
| Drugbank entries | Show/Hide entries for Ibuprofen |
| Comment | The cyclooxygenase inhibitor Ibuprofen (iso-butyl-propanoic-phenolic acid), which can activate PPARG, has been demonstrated to significantly reduce amyloid pathology and reduce microglial-mediated inflammation in a mouse model of AD, potentially via PPARG signaling. |
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Formal Description Interaction-ID: 35957 |
drug/chemical compound decreases_activity of phenotype Abeta pathology |
| Drugbank entries | Show/Hide entries for Ibuprofen |
| Comment | PPARG agonists have been shown to reduce Abeta plaque burden and Abeta42 (a specifically toxic form of Abeta) levels in the brain by approximately 20-25%, restore insulin responsiveness and lower glucocorticoid levels in mouse models of AD. |
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Formal Description Interaction-ID: 35961 |
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| Comment | PPARG agonists have been shown to reduce Abeta plaque burden and Abeta42 (a specifically toxic form of Abeta) levels in the brain by approximately 20-25%, restore insulin responsiveness and lower glucocorticoid levels in mouse models of AD. |
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Formal Description Interaction-ID: 35963 |
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| Comment | PPARG agonists have been shown to reduce Abeta plaque burden and Abeta42 (a specifically toxic form of Abeta) levels in the brain by approximately 20-25%, restore insulin responsiveness and lower glucocorticoid levels in mouse models of AD. |
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Formal Description Interaction-ID: 35967 |
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| Comment | PPARG agonists have been shown to reduce Abeta plaque burden and Abeta42 (a specifically toxic form of Abeta) levels in the brain by approximately 20-25%, restore insulin responsiveness and lower glucocorticoid levels in mouse models of AD. |
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Formal Description Interaction-ID: 35968 |
drug/chemical compound PPARG agonist decreases_activity of |
| Comment | PPARG also transcriptionally induces IDE expression, which could explain the effectiveness of PPARG agonists in treating both type 2 DM and AD. |
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Formal Description Interaction-ID: 35971 |
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| Drugbank entries | Show/Hide entries for PPARG or IDE |
| Comment | PPARD, which is expressed at higher levels in the brain than PPARG, also plays a role in regulating lipid and glucose metabolism. |
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Formal Description Interaction-ID: 35975 |
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| Drugbank entries | Show/Hide entries for PPARD |
| Comment | PPARD, which is expressed at higher levels in the brain than PPARG, also plays a role in regulating lipid and glucose metabolism. |
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Formal Description Interaction-ID: 35983 |
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| Drugbank entries | Show/Hide entries for PPARD |
| Comment | PPARD, which is expressed at higher levels in the brain than PPARG, also plays a role in regulating lipid and glucose metabolism. |
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Formal Description Interaction-ID: 35984 |
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| Drugbank entries | Show/Hide entries for PPARD |
| Comment | The PPARD agonist, GW742, reduced amyloid burden, an effect thought to be mediated by alterations in amyloid clearance. |
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Formal Description Interaction-ID: 36001 |
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| Comment | AD patients with significant weight loss display lower plasma leptin levels than weightstable AD patients, and disruption of homeostasis between leptin and cortisol is also observed in some AD patients. |
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Formal Description Interaction-ID: 36007 |
phenotype cooccurs with phenotype |
| Comment | AD patients with significant weight loss display lower plasma leptin levels than weightstable AD patients, and disruption of homeostasis between leptin and cortisol is also observed in some AD patients. |
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Formal Description Interaction-ID: 36024 |
disease affects_activity of process homeostasis between leptin and cortisol |
| Comment | Lower plasma leptin levels were associated with a higher risk of incident AD. Leptin may be directly involved in the development of AD symptoms by exerting effects on the brain, as high expression of leptin receptors are found in the hippocampus, suggesting that leptin plays a role in controlling learning and memory. Leptin - besides its role in energy regulation - may directly regulate the behavioral and pathological progression of AD. |
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Formal Description Interaction-ID: 36037 |
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| Comment | Lower plasma leptin levels were associated with a higher risk of incident AD. Leptin may be directly involved in the development of AD symptoms by exerting effects on the brain, as high expression of leptin receptors are found in the hippocampus, suggesting that leptin plays a role in controlling learning and memory. |
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Formal Description Interaction-ID: 36038 |
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| Comment | Leptin treatment can promote Abeta clearance by reducing beta-secretase activity and increasing ApoE-dependent Abeta uptake, and it also improves memory performance in AD animal models. |
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Formal Description Interaction-ID: 36039 |
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| Comment | Leptin treatment can promote Abeta clearance by reducing beta-secretase activity and increasing ApoE-dependent Abeta uptake, and it also improves memory performance in AD animal models. |
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Formal Description Interaction-ID: 36043 |
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| Drugbank entries | Show/Hide entries for BACE1 |
| Comment | Leptin treatment can promote Abeta clearance by reducing beta-secretase activity and increasing ApoE-dependent Abeta uptake, and it also improves memory performance in AD animal models. |
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Formal Description Interaction-ID: 36044 |
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| Drugbank entries | Show/Hide entries for APOE |
| Comment | Leptin treatment can promote Abeta clearance by reducing beta-secretase activity and increasing ApoE-dependent Abeta uptake, and it also improves memory performance in AD animal models, e.g. Leptin administration improves memory in SAMP-8 mice, an accelerated senescence rodent model that develops amyloid plaques. |
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Formal Description Interaction-ID: 36045 |
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| Comment | Leptin can also reduce tau phosphorylation through inactivation of GSK3B. |
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Formal Description Interaction-ID: 36085 |
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| Comment | Leptin can also reduce tau phosphorylation through inactivation of GSK3B. |
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Formal Description Interaction-ID: 36086 |
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| Drugbank entries | Show/Hide entries for GSK3B |
| Comment | Direct administration of leptin into the brain has been observed to facilitate hippocampal long-term potentiation. |
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Formal Description Interaction-ID: 36088 |
gene/protein increases_activity of process |
| Comment | Circulating ghrelin binds to neurons of the hippocampal formation, promoting dendritic spine formation and generation of long-term potentiation (LTP). |
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Formal Description Interaction-ID: 36093 |
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| Comment | Circulating ghrelin binds to neurons of the hippocampal formation, promoting dendritic spine formation and generation of long-term potentiation (LTP). |
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Formal Description Interaction-ID: 36094 |
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| Comment | Circulating ghrelin binds to neurons of the hippocampal formation, promoting dendritic spine formation and generation of long-term potentiation (LTP). |
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Formal Description Interaction-ID: 36095 |
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| Comment | Targeted disruption of ghrelin signaling resulted in a decreased number of spine synapses in the stratum radiatum and impaired performance in behavioral memory testing, both of which were rapidly restored by ghrelin administration. |
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Formal Description Interaction-ID: 36098 |
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| Comment | Ghrelin levels in the brain are altered in some Alzheimer's patients, suggesting that changes to the ghrelin signaling system may indeed contribute to AD pathophysiology. |
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Formal Description Interaction-ID: 36099 |
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| Comment | One clinical study demonstrated that some AD patients have elevated levels of adiponectin in both plasma and cerebrospinal fluid (CSF), suggesting that it may play a role in mediating AD progression, possibly through its effects on peripheral or brain metabolism. |
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Formal Description Interaction-ID: 36117 |
disease increases_activity of phenotype |
| Comment | Elevated interleukin-6 has been detected in the brains of some AD patients, and that treatment with adiponectin can reduce the secretion of the centrally active interleukin-6 from brain endothelial cells. |
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Formal Description Interaction-ID: 36118 |
disease increases_activity of |
| Comment | Elevated interleukin-6 has been detected in the brains of some AD patients, and that treatment with adiponectin can reduce the secretion of the centrally active interleukin-6 from brain endothelial cells. |
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Formal Description Interaction-ID: 36148 |
gene/protein decreases_activity of process |
| Comment | GLP-1 and exendin-4, a natural and stable long-acting analogue of GLP-1, possess neurotrophic properties and protect neurons against Abeta and oxidative insults. |
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Formal Description Interaction-ID: 36184 |
gene/protein decreases_activity of gene/protein |
| Comment | GLP-1 and exendin-4, a natural and stable long-acting analogue of GLP-1, possess neurotrophic properties and protect neurons against Abeta and oxidative insults. |
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Formal Description Interaction-ID: 36185 |
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| Comment | GLP-1 and exendin-4, a natural and stable long-acting analogue of GLP-1, possess neurotrophic properties and protect neurons against Abeta and oxidative insults. |
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Formal Description Interaction-ID: 36186 |
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| Comment | GLP-1 and exendin-4, a natural and stable long-acting analogue of GLP-1, possess neurotrophic properties and protect neurons against Abeta and oxidative insults. |
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Formal Description Interaction-ID: 36187 |
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| Comment | GLP-1 can reduce amyloid-beta peptide levels in vivo and decreases levels of amyloid precursor protein in cultured neuronal cells, implying that GLP-1 could be effective at reducing plaque load in AD. |
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Formal Description Interaction-ID: 36191 |
gene/protein decreases_quantity of gene/protein |
| Drugbank entries | Show/Hide entries for APP |
| Comment | GLP-1 receptor agonists protect neurons against Abeta and glutamate-induced apoptosis in cells and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. |
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Formal Description Interaction-ID: 36341 |
drug/chemical compound GLP1R agonist decreases_activity of gene/protein |
| Comment | GLP-1 receptor agonists protect neurons against Abeta and glutamate-induced apoptosis in cells and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. |
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Formal Description Interaction-ID: 36342 |
drug/chemical compound GLP1R agonist increases_activity of |
| Comment | GLP-1 receptor agonists protect neurons against Abeta and glutamate-induced apoptosis in cells and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. |
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Formal Description Interaction-ID: 36343 |
drug/chemical compound GLP1R agonist decreases_activity of process |
| Comment | GLP-1 receptor agonists protect neurons against Abeta and glutamate-induced apoptosis in cells and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. |
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Formal Description Interaction-ID: 36344 |
drug/chemical compound GLP1R agonist decreases_activity of phenotype cholinergic neuron atrophy |
| Comment | Attenuation of the activity levels of dipeptidyl peptidase 4 (DPP-4, cleaves and inactivates GLP-1), can stabilize the plasma levels of the bioactive GLP-1. |
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Formal Description Interaction-ID: 36345 |
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| Drugbank entries | Show/Hide entries for DPP4 |
| Comment | Attenuation of the activity levels of dipeptidyl peptidase 4 (DPP-4, cleaves and inactivates GLP-1), can stabilize the plasma levels of the bioactive GLP-1. |
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Formal Description Interaction-ID: 36346 |
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| Drugbank entries | Show/Hide entries for DPP4 |
| Comment | GCG is cleaved into 8 chains. One chain is GLP1. |
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Formal Description Interaction-ID: 36347 |
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| Comment | Sitagliptin, a DPP-4 inhibitor, could significantly delay some forms of AD pathology, including amyloid deposition, when administrated early in the disease course in a mouse model of AD. |
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Formal Description Interaction-ID: 36348 |
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| Drugbank entries | Show/Hide entries for Sitagliptin or DPP4 |
| Comment | Sitagliptin, a DPP-4 inhibitor, could significantly delay some forms of AD pathology, including amyloid deposition, when administrated early in the disease course in a mouse model of AD. |
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Formal Description Interaction-ID: 36349 |
drug/chemical compound decreases_activity of disease |
| Drugbank entries | Show/Hide entries for Sitagliptin |
| Comment | Sitagliptin, a DPP-4 inhibitor, could significantly delay some forms of AD pathology, including amyloid deposition, when administrated early in the disease course in a mouse model of AD. |
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Formal Description Interaction-ID: 36350 |
drug/chemical compound decreases_quantity of phenotype |
| Drugbank entries | Show/Hide entries for Sitagliptin |
| Comment | BDNF signaling has been shown to be impaired in AD, which could be relevant considering the neurological and metabolic abnormalities noted in AD. |
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Formal Description Interaction-ID: 36351 |
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| Comment | Studies have demonstrated low brain BDNF mRNA expression in patients with AD, including the hippocampus, neocortex and in the nucleus basalis of Meynert. |
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Formal Description Interaction-ID: 36354 |
disease decreases_expression of gene/protein |
| Comment | Sorting protein-related receptor with A-type repeats (SORLA) regulates APP intracellular trafficking and processing into Abeta, and when overexpressed, can reduce amyloid plaque formation. |
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Formal Description Interaction-ID: 36355 |
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| Drugbank entries | Show/Hide entries for APP |
| Comment | Sorting protein-related receptor with A-type repeats (SORLA) regulates APP intracellular trafficking and processing into Abeta, and when overexpressed, can reduce amyloid plaque formation. |
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Formal Description Interaction-ID: 36357 |
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| Drugbank entries | Show/Hide entries for APP |
| Comment | Sorting protein-related receptor with A-type repeats (SORLA) regulates APP intracellular trafficking and processing into Abeta, and when overexpressed, can reduce amyloid plaque formation. |
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Formal Description Interaction-ID: 36358 |
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| Comment | BDNF was found to be a major inducer of SORLA gene transcription through the extracellular regulated kinase (ERK) pathway. It is possible that a gradual decrease in BDNF levels may contribute to the increase in the risk of developing AD with advancing age. |
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Formal Description Interaction-ID: 36360 |
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