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  3. PubMed:21718217

PubMed: 21718217

Title
Nuclear receptors as therapeutic targets for Alzheimer's disease.
Journal
Expert opinion on therapeutic targets
Volume
15
Issue
None
Pages
1085-97
Date
2011-09-01
Authors
Landreth GE | Mandrekar-Colucci S

Evidence 038ba0093c
JSON

Importantly, this study utilized the LXR agonist, GW3965, to activate the LXRs and induce the expression of both ApoE and ABCA1.

a(CHEBI:"GW 3965") directlyIncreases act(p(HGNC:NR1H3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"GW 3965") increases p(HGNC:APOE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"GW 3965") increases p(HGNC:ABCA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence a9a1bca61c
JSON

Similarly, stimulation of microglia with the LXR agonist, GW3965, acts simultaneously to suppress inflammation and promote fibrillar Ab stimulated phagocytosis [47].

a(CHEBI:"GW 3965") increases act(p(HGNC:NR1H3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:"GW 3965") decreases path(MESH:Inflammation) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:"GW 3965") increases act(a(HBP:HBP00038)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:"GW 3965") increases bp(GO:phagocytosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

act(a(HBP:HBP00038)) increases bp(GO:phagocytosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence e492c46621
JSON

Significantly, a 4-month treatment of Tg2576 mice with GW3965 reduced plaque deposition by > 50% and improved contextual memory in these animals [13].

a(CHEBI:"GW 3965") decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"GW 3965") increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 960f705025
JSON

The PPAR-d agonist GW501516 induced expression of ABCA1 and apolipoprotein A1, a peripheral lipid transporter, in macrophages [71].

a(CHEBI:"GW 501516") increases act(p(HGNC:PPARD)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"GW 501516") increases p(HGNC:ABCA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"GW 501516") increases p(HGNC:APOA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 665716675c
JSON

In a study reported by Kalinin et al., treatment of 5xFAD mice with the PPAR-d agonist, GW742, resulted in decreased plaque burden and an increase in the expression of two Ab proteases, neprilysin and IDE [72].

a(CHEBI:"GW 501516") decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"GW 501516") increases p(HGNC:MME) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"GW 501516") increases p(HGNC:IDE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 64e07c0df7
JSON

ATRA not only activates RXR but also activates the retinoic acid receptor.

a(CHEBI:"all-trans-retinoic acid") increases act(p(FPLX:RXR)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"all-trans-retinoic acid") increases act(p(FPLX:RAR)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence efa5c47246
JSON

Treatment of 5-month-old APP/PS1 mice for 8 weeks with ATRA (20 mg/kg/day) resulted in significant decreases in Ab deposition and tau phosphorylation in these mice. Additionally, it attenuated memory deficits seen in the Morris water maze [77].

a(CHEBI:"all-trans-retinoic acid") decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:"all-trans-retinoic acid") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:"all-trans-retinoic acid") increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence d3f77afd3a
JSON

More recently, a naturally occurring RXR agonist, honokiol, has been identified. This agonist is capable of activating RXR/LXR heterodimers and has been shown to induce the expression of ABCA1 and ApoE and should be tested in AD models [75,78].

a(CHEBI:Honokiol) increases act(p(FPLX:RXR)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:Honokiol) increases act(complex(p(FPLX:RXR), p(HGNC:NR1H3))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:Honokiol) increases p(HGNC:APOE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:Honokiol) increases p(HGNC:ABCA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 64a0a34caf
JSON

Bexarotene is a highly specific RXR agonist and is currently FDA approved with a favorable side effect profile. Studies in our laboratory have shown that treatment of APP/ PS1 animals with bexarotene for only 3 days results in a dramatic induction of ApoE and ABCA1 and the rapid reversal of AD-associated pathological hallmarks including reduction in amyloid deposition and deficits in behavior as well as neural networks.

a(CHEBI:bexarotene) increases act(p(FPLX:RXR)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:bexarotene) increases p(HGNC:APOE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:bexarotene) increases p(HGNC:ABCA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:bexarotene) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:bexarotene) increases bp(GO:behavior) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence a86cd20b93
JSON

LXR receptors are activated by oxysterols, most prominently hydroxylated forms of cholesterol, and play a critical role in the control of whole body cholesterol homeostasis, as well as exerting potent anti-inflammatory actions [26].

a(CHEBI:cholesterol) increases act(p(HGNC:NR1H3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:oxysterol) increases act(p(HGNC:NR1H3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 2d6986d9ee
JSON

LXR receptors are activated by oxysterols, most prominently hydroxylated forms of cholesterol, and play a critical role in the control of whole body cholesterol homeostasis, as well as exerting potent anti-inflammatory actions [26].

a(CHEBI:oxysterol) increases act(p(HGNC:NR1H3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

bp(GO:"cholesterol homeostasis") association p(HGNC:NR1H3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

bp(GO:"negative regulation of inflammatory response") association p(HGNC:NR1H3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:NR1H3) association bp(GO:"cholesterol homeostasis") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:NR1H3) association bp(GO:"negative regulation of inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 41a525e257
JSON

The synthetic TZD PPAR-g agonists are widely prescribed for the treatment of type 2 diabetes mellitus, and have also been shown to be efficacious in a number of CNS disease models [21]. Currently, two TZD agonists, Actos (pioglitazone) and Avandia (rosiglitazone), are FDA approved for the treatment of diabetes.

a(CHEBI:pioglitazone) increases act(p(HGNC:PPARG)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:pioglitazone) decreases path(MESH:"Diabetes Mellitus, Type 2") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) increases act(p(HGNC:PPARG)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) decreases path(MESH:"Diabetes Mellitus, Type 2") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence c1ae607d10
JSON

When a higher dose of pioglitazone (7 days/40 mg/kg/day) was used in 10-monthold transgenic mice overexpressing the APP V717I mutation, a 20-- 25% decrease in plaque burden was observed with significant reduction in Ab42 levels within the brains of these animals [61].

a(CHEBI:pioglitazone) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:pioglitazone) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence db42f55e1c
JSON

Furthermore, the treatment of APP/PS1 mouse model of AD with pioglitazone (80 mg/kg/day) for 9 days lowered plaque burden by ~ 50% and reversed behavioral deficits in contextual fear conditioning assay.

a(CHEBI:pioglitazone) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:pioglitazone) increases bp(GO:behavior) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 8ff1e59438
JSON

Significantly, the levels of ABCA1 and ApoE were elevated in the brains of these animals [66].

a(CHEBI:pioglitazone) increases p(MGI:Abca1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:pioglitazone) increases p(MGI:Apoe) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 1c41e4dbb9
JSON

In this study, pioglitazone treatment was shown to improve memory and cognition in these patients [67,68].

a(CHEBI:pioglitazone) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:pioglitazone) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence c9ea191a60
JSON

Pedersen and Flynn examined the effects of rosiglitazone and found that activation of PPAR-g ameliorated behavioral deficits in the Tg2576 AD mouse model. However, these animals displayed no changes in plaque pathology, but had reduced brain Ab42 levels.

a(CHEBI:rosiglitazone) increases act(p(HGNC:PPARG)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) increases bp(GO:behavior) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) causesNoChange a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 4be4415b0b
JSON

LXR activation increased the ApoE particle size of all human ApoE isoforms, suggesting that activation of this pathways may enhance Ab clearance regardless of the ApoE allele expressed [13].

act(p(HGNC:NR1H3)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

act(p(HGNC:NR1H3)) increases act(p(HGNC:APOE)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

act(p(HGNC:APOE)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 912eb97c60
JSON

These animals were treated with a low dose of rosiglitazone (3 mg/kg/ day) for 12 weeks and evaluated for plaque deposition and behavior. These animals displayed an approximate 50% decrease in amyloid deposition, a decrease in Ab oligomers, preservation of pre and postsynaptic proteins and the attenuation of cognitive deficits in the Morris water maze.

a(CHEBI:rosiglitazone) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) increases bp(GO:"learning or memory") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 24a064d1d8
JSON

The authors argue that the effects of rosiglitazone were due to the activation of the wnt signaling cascade which they show by an increase in b-catenin expression and a decrease in GSK-3b levels [63].

a(CHEBI:rosiglitazone) increases p(MGI:Ctnnb1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:rosiglitazone) decreases p(MGI:Gsk3b) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 72dfe83719
JSON

While the authors did not detect an increase in ApoE levels in the treated animals, they did observe a modest increase in ABCA1 levels and argue that the enhanced Ab clearance could be attributed to an increase in lipidation of ApoE by ABCA1 [64].

a(CHEBI:rosiglitazone) increases p(MGI:Abca1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 41f21f145d
JSON

A Phase II clinical trial in which patients were treated with rosiglitazone for 6 months showed improvements in attention and memory retention, but only in patients who did not have an APOE4 allele.

a(CHEBI:rosiglitazone) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:rosiglitazone) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 80b4c42adc
JSON

AD is a chronic neurodegenerative disease characterized by the progressive deposition of the amyloid b (Ab) in the parenchyma of the brain.

a(HBP:HBP00018) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") association a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence dd554dd68b
JSON

It has been postulated that soluble or small oligomeric forms of Ab have deleterious effects in the brain, inducing impaired synaptic function and promoting neuronal degeneration [5].

a(HBP:HBP00022) decreases bp(GO:"synaptic signaling") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(HBP:HBP00022) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(HBP:HBP00074) decreases bp(GO:"synaptic signaling") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(HBP:HBP00074) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 946fe71f3f
JSON

The ApoE4 allele is most important genetic risk factor for AD, while the ApoE2 allele is thought to be protective.

a(HBP:HBP00030) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00030) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence dfa5bf8465
JSON

Mice expressing the ApoE4 isoform exhibited higher levels of Ab deposition in comparison to ApoE3 or ApoE2 expressing animals [36].

a(HBP:HBP00030) increases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 25883fc57f
JSON

The deposition of fibrillar Ab in the AD brain results in the recruitment of microglia to the plaques owing to their expression of CCL2, which acts to attract microglia [82].

a(HBP:HBP00038) increases p(HGNC:CCL2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(HBP:HBP00038) increases bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:CCL2) increases bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 6f41241991
JSON

The development of dense-core amyloid plaques is associated with a robust immune response mediated by microglial cells.

a(HBP:HBP00089) association bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(GO:"microglial cell activation") association a(HBP:HBP00089) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 5da2d8427c
JSON

The appearance of amyloid deposition in the AD brain coincides with a dramatic phenotypic activation of microglial cells in the surrounding area.

a(HBP:HBP00089) positiveCorrelation bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(GO:"microglial cell activation") positiveCorrelation a(HBP:HBP00089) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence ba0a0d8811
JSON

The plaque-associated microglia secrete a variety of cytotoxic species including the inflammatory cytokines, INF-g, TNF-a, IL-1b and IL-6 and chemokines, most prominently CCL2 [10-12].

a(HBP:HBP00089) increases sec(p(HGNC:IFNG)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00089) increases sec(p(HGNC:TNF)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00089) increases sec(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00089) increases sec(p(HGNC:IL6)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00089) increases sec(p(HGNC:CCL2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 7c7bfe2eaa
JSON

The M2c macrophages are thought to be in an ‘acquired deactivation’ state induced by IL-10, TGF-b, glucocorticoids or contact with apoptotic cells, and are associated with a suppression of the innate immune response.

a(MESH:Glucocorticoids) decreases a(MESH:Macrophages) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:IL10) decreases a(MESH:Macrophages) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:TGFB1) decreases a(MESH:Macrophages) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 30825cfcde
JSON

PPARs have been shown to play essential roles in energy metabolism, adipocyte differentiation, insulin sensitization and tumor suppression.

bp(GO:"fat cell differentiation") association p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

bp(GO:"response to insulin") association p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

bp(GO:"response to tumor cell") association p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

bp(MESH:"Energy Metabolism") association p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(FPLX:PPAR) association bp(MESH:"Energy Metabolism") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(FPLX:PPAR) association bp(GO:"fat cell differentiation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(FPLX:PPAR) association bp(GO:"response to insulin") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(FPLX:PPAR) association bp(GO:"response to tumor cell") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence a6045dfe22
JSON

PPARs have been shown to play essential roles in energy metabolism, adipocyte differentiation, insulin sensitization and tumor suppression.

bp(GO:"fat cell differentiation") positiveCorrelation p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

bp(GO:"response to insulin") positiveCorrelation p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

bp(GO:"response to tumor cell") positiveCorrelation p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

bp(MESH:"Energy Metabolism") positiveCorrelation p(FPLX:PPAR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(FPLX:PPAR) positiveCorrelation bp(MESH:"Energy Metabolism") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(FPLX:PPAR) positiveCorrelation bp(GO:"fat cell differentiation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(FPLX:PPAR) positiveCorrelation bp(GO:"response to insulin") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(FPLX:PPAR) positiveCorrelation bp(GO:"response to tumor cell") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 5194c612f6
JSON

PPAR-b/-d is the most abundant isoform and plays a role in fatty acid oxidation [22].

bp(GO:"fatty acid oxidation") association p(HGNC:PPARD) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:PPARD) association bp(GO:"fatty acid oxidation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 845390c859
JSON

PPAR-g is involved in lipid storage, insulin sensitivity and energy metabolism and has been shown to promote adipocyte differentiation [21].

bp(GO:"lipid storage") association p(HGNC:PPARG) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

bp(GO:"response to insulin") association p(HGNC:PPARG) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

bp(MESH:"Energy Metabolism") association p(HGNC:PPARG) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:PPARG) association bp(MESH:"Energy Metabolism") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:PPARG) increases bp(GO:"fat cell differentiation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:PPARG) association bp(GO:"response to insulin") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:PPARG) association bp(GO:"lipid storage") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 7ad65ed30e
JSON

PPAR-g is involved in lipid storage, insulin sensitivity and energy metabolism and has been shown to promote adipocyte differentiation [21].

bp(MESH:"Energy Metabolism") association p(HGNC:PPARGC1A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:PPARGC1A) association bp(MESH:"Energy Metabolism") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:PPARGC1A) association path(MESH:"Insulin Resistance") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:PPARGC1A) increases bp(GO:"fat cell differentiation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

path(MESH:"Insulin Resistance") association p(HGNC:PPARGC1A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 89f9079f6a
JSON

They act as dominant regulators of lipid metabolism through their ability to transactivate genes encoding enzymes of lipid metabolism, providing a key linkage between the diet and the genome.

p(FPLX:PPAR) regulates bp(GO:"lipid metabolic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

Evidence c5be711952
JSON

Indeed, treatment of AD mouse models with LXR or PPAR agonists has resulted in the suppression of microglial activation [44,45,47,59,63].

act(p(FPLX:PPAR)) decreases bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

act(p(HGNC:NR1H3)) decreases bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 4bbf207303
JSON

RXR activation by numerous ligands has shown to increase levels of both ApoE and ABCA1 in vitro [74-76].

act(p(FPLX:RXR)) increases p(HGNC:APOE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

act(p(FPLX:RXR)) increases p(HGNC:ABCA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 16b4cf5aba
JSON

In the past decade, drugs targeting the NRs, peroxisome proliferator-activated receptor g (PPARg) and liver X receptor (LXR) have shown to ameliorate pathogenesis in animal models of AD.

act(p(HGNC:NR1H3)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

act(p(HGNC:PPARG)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence fcf55b6a5c
JSON

Recently, they have been shown to promote the degradation of the Ab peptides in the brain by activating genes responsible for reverse cholesterol transport [13].

act(p(HGNC:NR1H3)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

act(p(HGNC:NR1H3)) increases bp(GO:"reverse cholesterol transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

act(p(HGNC:PPARG)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

act(p(HGNC:PPARG)) increases bp(GO:"reverse cholesterol transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence d3f1147995
JSON

Activation of these receptors has been shown to suppress microglial-mediated inflammatory responses both in vitro and in vivo.

act(p(HGNC:NR1H3)) decreases bp(GO:"microglial cell activation involved in immune response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

act(p(HGNC:PPARG)) decreases bp(GO:"microglial cell activation involved in immune response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 261259e41f
JSON

Numerous studies have shown that both PPAR-g and LXRs induce the expression of ApoE and ABCA1 and it is through the expression of these proteins that they exert their effects on amyloid pathology.

p(HGNC:NR1H3) increases p(HGNC:APOE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:NR1H3) increases p(HGNC:ABCA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:PPARG) increases p(HGNC:APOE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:PPARG) increases p(HGNC:ABCA1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 30455a46e8
JSON

A different result was reported by Vanmierlo et al. who found that LXR agonist treatment resulted in restoration of memory, but did not find a change in plaque burden [48].

act(p(HGNC:NR1H3)) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 389c7a57db
JSON

The ApoE4 allele is most important genetic risk factor for AD, while the ApoE2 allele is thought to be protective.

p(HBP:HBP00030) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

path(MESH:"Alzheimer Disease") association p(HBP:HBP00030) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence bdb07c325b
JSON

The loss of abca1 resulted in not only the reduction of ApoE levels but also a paradoxical increase in Ab deposition in the brain parenchyma of these animals owing to enhanced deposition of poorly lipidated ApoE in the brain [50-52].

p(HGNC:ABCA1) increases p(HGNC:APOE) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:ABCA1) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 3661d2ce48
JSON

The Ab peptide is generated by the sequential cleavage of the amyloid precursor protein (APP) by the b and g secretases, resulting in the generation of peptides 40 or 42 amino acids in length [2].

p(HGNC:APH1A) decreases p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:APH1A) increases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:BACE1) decreases p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:BACE1) increases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 705a207f7e
JSON

ApoE acts to scaffold the formation of high-density lipoproteins (HDL) that function to transport cholesterol and lipids throughout the body and in the brain.

p(HGNC:APOE) increases a(CHEBI:"high-density lipoprotein") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 558e9a30f6
JSON

They were able to show that the lipidation of ApoE enhanced the degradation of soluble species of Ab by neprilysin in the endolytic compartments of microglia as well as extracellularly through the actions of the insulindegrading enzyme (IDE) [13].

p(HGNC:APOE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

p(HGNC:IDE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence d812ecb0b3
JSON

PPAR-a is known to regulate lipid oxidation but is not highly expressed in the brain [20].

p(HGNC:PPARA) regulates bp(GO:"lipid oxidation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

p(HGNC:PPARA) regulates bp(MESH:"Lipid Peroxidation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 0f85da5998
JSON

PPAR-d activation has also been shown to promote reverse cholesterol transport.

act(p(HGNC:PPARD)) increases bp(GO:"reverse cholesterol transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence f62b4e9926
JSON

PPAR-d activation has also been shown to have robust anti-inflammatory actions [73].

act(p(HGNC:PPARD)) increases bp(GO:"negative regulation of inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 91eab7661a
JSON

Activation of PPAR-g or PPAR-d has been shown to induce Arg1 and IL-4 expression [105,106].

act(p(HGNC:PPARD)) increases p(HGNC:ARG1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

act(p(HGNC:PPARD)) increases p(HGNC:IL4) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

act(p(HGNC:PPARG)) increases p(HGNC:ARG1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

act(p(HGNC:PPARG)) increases p(HGNC:IL4) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 713a2f5ba0
JSON

Additionally, PPAR-g can also induce the expression of LXRa creating a metabolically linked cycle.

p(HGNC:PPARG) increases p(HGNC:NR1H3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence d45d1ce38b
JSON

Conversely, overexpression of ABCA1 in a mouse model of AD was shown to decrease both soluble and fibrillar pools of Ab in 12-month-old mice and reduce plaque burden [53].

p(MGI:Abca1) decreases a(HBP:HBP00038) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(MGI:Abca1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 2a9f6386b8
JSON

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly.

path(MESH:"Alzheimer Disease") increases path(MESH:Dementia) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 8000bd644b
JSON

In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101].

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:ARG1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:CHI3L1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

r(HGNC:ARG1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

r(HGNC:CHI3L1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.