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  3. PubMed:11230871

PubMed: 11230871

Title
Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications.
Journal
Biological psychiatry
Volume
49
Issue
None
Pages
200-10
Date
2001-02-01
Authors
Nordberg A

Evidence 351df523e7
JSON

beta-Amyloid (Abeta) is also an important factor, which may initiate and promote AD (Selkoe 1999)

a(CHEBI:"amyloid-beta") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

Evidence e72e34197e
JSON

Administration of the nicotinic antagonist mecamylamine to elderly subjects and AD patients has produced cognitive impairment (Newhouse and Kelton 2000)

a(CHEBI:Mecamylamine) decreases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 2d71de02fe
JSON

Nerve growth factor intraventricularly administered to AD patients for 3 months resulted in an increased [11C]nicotine binding (Eriksdotter-Jo¨nhagen et al 1998), whereas treatment with the 5-HT3 blocker ondansetron showed a decreased number of cortical nAChRs (Nordberg et al 1997)

a(CHEBI:Ondansetron) decreases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(MESH:"Nerve Growth Factor") increases complex(a(CHEBI:nicotine), p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence ab3526f553
JSON

Cholinergic therapy is based on the assumption that low levels of acetylcholine are responsible for the cognitive decline associated with AD

a(CHEBI:acetylcholine) negativeCorrelation bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:cognition) negativeCorrelation a(CHEBI:acetylcholine) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence c81dfb45ed
JSON

It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)

a(CHEBI:donepezil) increases act(p(HGNC:ACHE)) View Subject | View Object

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a(CHEBI:galanthamine) increases act(p(HGNC:ACHE)) View Subject | View Object

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a(CHEBI:rivastigmine) increases act(p(HGNC:ACHE)) View Subject | View Object

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a(CHEBI:tacrine) increases act(p(HGNC:ACHE)) View Subject | View Object

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Evidence 03388f1160
JSON

Estrogen, which in epidemiologic studies has been shown to reduce the risk of AD (Henderson 1997), has in experimental studies in PC 12 cells shown neuroprotective effects against Abeta toxicity that are at least partly mediated by the alpha7 subtype nAChR (Svensson and Nordberg 1998)

a(CHEBI:estrogen) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"alpha-7-containing nAChR") regulates act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 7f9e5ef120
JSON

Activation of the nAChR modulates the release of several neurotransmitters (Kaiser et al 2000; Wonnacott 1997) that mediate important physiologic mechanisms including cognitive functions

a(CHEBI:neurotransmitter) association bp(GO:cognition) View Subject | View Object

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bp(GO:cognition) association a(CHEBI:neurotransmitter) View Subject | View Object

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act(p(FPLX:CHRN)) regulates tloc(a(CHEBI:neurotransmitter), fromLoc(GO:intracellular), toLoc(GO:"extracellular region")) View Subject | View Object

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Evidence 36cc72cfd3
JSON

The potential therapeutic benefit of nAChR stimulation in AD is based upon the fact that nicotine improves memory in animals, healthy subjects, and AD patients (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Rusted and Warburton 1992)

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 5e38da9f4c
JSON

Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992)

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

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases bp(GO:learning) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases path(MESH:Attention) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 01bb6dfc3d
JSON

Since an enhanced activity of acetylcholinesterase has been measured in cerebrospinal fluid following long-term treatment with tacrine (Nordberg et al 1999), possibly as a result of an increased acetylcholinesterase gene expression, it might be an advantage to use drugs interacting with nAChRs

a(CHEBI:tacrine) increases act(p(HGNC:ACHE)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid

Evidence af7a259f32
JSON

In addition, PET studies also have revealed an improvement in nAChRs in AD patients during long-term treatment with cholinesterase inhibitors such as tacrine and NXX- 066 (Nordberg 2000; Nordberg et al 1992, 1998)

a(CHEBI:tacrine) increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(PUBCHEM:132228) increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 0ee23c35af
JSON

Positron emission tomography studies have revealed a reduced cortical acetylcholinesteserase activity in AD patients (Iyo et al 1997; Kuhl et al 1999)

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:ACHE)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 3cb131522b
JSON

The levels of alpha4 and alpha7 nAChR mRNA showed a decrease with aging, whereas the levels of alpha3 mRNA were unchanged in the elderly brain relative to the fetal brain (Hellstro¨m-Lindahl et al 1998)

bp(GO:aging) causesNoChange r(HGNC:CHRNA3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

bp(GO:aging) negativeCorrelation a(HBP:"alpha-4-containing nAChR") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(HBP:"alpha-4-containing nAChR") negativeCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(HBP:"alpha-7-containing nAChR") negativeCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

bp(GO:aging) negativeCorrelation a(HBP:"alpha-7-containing nAChR") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 08da1f3af0
JSON

A decrease in protein levels of the alpha4 nAChR but not of the alpha3 and alpha7 nAChRs was reported by Martin-Ruiz et al (1999)

a(HBP:"alpha-4-containing nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation a(HBP:"alpha-4-containing nAChR") View Subject | View Object

Appears in Networks:

Evidence 8489a9f967
JSON

Lee et al (2000) recently also reported a significant decrease in the alpha7 nAChR protein level of the AD hippocampus

a(HBP:"alpha-7-containing nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation a(HBP:"alpha-7-containing nAChR") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 70ab6e6d26
JSON

Interestingly, a reduction in the protein level of alpha7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the alpha4 nAChR protein level (Guan et al 1999)

a(HBP:"alpha-7-containing nAChR") negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

path(MESH:Schizophrenia) negativeCorrelation a(HBP:"alpha-7-containing nAChR") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

path(MESH:Schizophrenia) causesNoChange a(HBP:"alpha-4-containing nAChR") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

Evidence 72695efb88
JSON

Possible factors such as amyloid peptide accumulation, hyperphosphorylation of tau protein, oxidative stress, and modification of cell membrane during the development of AD may be related to decreased protein levels of nAChRs (Farooqui et al 1995; Smith et al 1996)

a(MESH:"Amyloid beta-Peptides") negativeCorrelation p(FPLX:CHRN) View Subject | View Object

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bp(GO:"response to oxidative stress") negativeCorrelation p(FPLX:CHRN) View Subject | View Object

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p(FPLX:CHRN) negativeCorrelation a(MESH:"Amyloid beta-Peptides") View Subject | View Object

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p(FPLX:CHRN) negativeCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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p(FPLX:CHRN) negativeCorrelation bp(GO:"response to oxidative stress") View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) negativeCorrelation p(FPLX:CHRN) View Subject | View Object

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Evidence 8af4827544
JSON

Experimental data suggest that the nAChRs might act as neuromodulators in communicative processes in the brain (Kaiser et al 2000; Lindstro¨m 1997; Wonnacott 1997)

a(MESH:"Neurotransmitter Agents") association p(FPLX:CHRN) View Subject | View Object

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p(FPLX:CHRN) association a(MESH:"Neurotransmitter Agents") View Subject | View Object

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Evidence 2c59e9995c
JSON

Recently, the nicotinic agonist ABT- 418 improved verbal learning and memory on a selective reminding task in AD patients (Potter et al 1999)

a(PUBCHEM:119380) increases path(MESH:"Verbal Learning") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(PUBCHEM:119380) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 15a19f4c42
JSON

The presynaptic vesicular acetylcholine transporter vesamicol ([123I]iodobenzovesamicol) has been used in vivo as a marker of presynaptic cholinergic activity in single photon emission computed tomography (SPECT) studies (Kuhl et al 1996)

a(PUBCHEM:5662) association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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bp(GO:"synaptic transmission, cholinergic") association a(PUBCHEM:5662) View Subject | View Object

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Evidence 9a29cb7469
JSON

A significant decrease in [3H]epibatidine binding has been observed with aging in the human cortical brain regions and cerebellum (Marutle et al 1998)

bp(GO:aging) negativeCorrelation complex(a(CHEBI:epibatidine), p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebellum
MeSH
Cerebral Cortex

complex(a(CHEBI:epibatidine), p(FPLX:CHRN)) negativeCorrelation bp(GO:aging) View Subject | View Object

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Annotations
MeSH
Cerebellum
MeSH
Cerebral Cortex

Evidence 6a385cf4a3
JSON

In addition, a marked reduction in the laminar distribution of [3H]epibatidine binding was observed in control cortical tissue with aging (Figure 1)

bp(GO:aging) negativeCorrelation complex(a(CHEBI:epibatidine), p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

complex(a(CHEBI:epibatidine), p(FPLX:CHRN)) negativeCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 84d8799e06
JSON

Interestingly enough, a considerable body of evidence exists to suggest that the nAChRs are involved in cognitive and memory functions (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Sahakian and Coull 1994)

p(FPLX:CHRN) association bp(GO:cognition) View Subject | View Object

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p(FPLX:CHRN) association bp(GO:memory) View Subject | View Object

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bp(GO:cognition) association p(FPLX:CHRN) View Subject | View Object

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bp(GO:memory) association p(FPLX:CHRN) View Subject | View Object

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Evidence e90a68b501
JSON

A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000)

bp(GO:cognition) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

act(p(HGNC:ACHE)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:ACHE)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence a63533aa5b
JSON

A significant correlation can be observed between cognitive function and nicotinic receptor binding (k2*) (Figure 3A)

bp(GO:cognition) association complex(a(CHEBI:nicotine), p(FPLX:CHRN)) View Subject | View Object

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complex(a(CHEBI:nicotine), p(FPLX:CHRN)) association bp(GO:cognition) View Subject | View Object

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Evidence 02473a74d1
JSON

Interestingly enough, lipid peroxidation has been shown to decrease the number of nAChRs in PC12 cells (Guan et al 2000a)

bp(MESH:"Lipid Peroxidation") decreases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:

Evidence d7cda8a97f
JSON

The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)

p(FPLX:CHRN) association path(MESH:"Alzheimer Disease") View Subject | View Object

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p(FPLX:CHRN) association path(MESH:"Parkinson Disease") View Subject | View Object

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p(FPLX:CHRN) association path(MESH:Schizophrenia) View Subject | View Object

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p(FPLX:CHRN) association path(MESH:"Tourette Syndrome") View Subject | View Object

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p(FPLX:CHRN) association path(MESH:Anxiety) View Subject | View Object

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p(FPLX:CHRN) association path(MESH:Depression) View Subject | View Object

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p(FPLX:CHRN) association path(MESH:Epilepsy) View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(FPLX:CHRN) View Subject | View Object

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path(MESH:"Parkinson Disease") association p(FPLX:CHRN) View Subject | View Object

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path(MESH:"Tourette Syndrome") association p(FPLX:CHRN) View Subject | View Object

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path(MESH:Anxiety) association p(FPLX:CHRN) View Subject | View Object

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path(MESH:Depression) association p(FPLX:CHRN) View Subject | View Object

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path(MESH:Epilepsy) association p(FPLX:CHRN) View Subject | View Object

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path(MESH:Schizophrenia) association p(FPLX:CHRN) View Subject | View Object

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Evidence 9589d2c846
JSON

A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from AD patients relative to age-matched healthy subjects (Nordberg and Winblad 1986)

p(FPLX:CHRN) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

Evidence 38159dec64
JSON

The cortical nAChR deficits significantly correlate with cognitive impairment in AD patients (Nordberg, in press; Nordberg et al 1995, 1997)

p(FPLX:CHRN) negativeCorrelation path(MESH:"Cognitive Dysfunction") View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

path(MESH:"Cognitive Dysfunction") negativeCorrelation p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

Evidence 7e4f07fc18
JSON

Significant reductions in the number of nAChRs were measured in cortical regions of Swedish APP 670/ 671 mutation (273% to 287%) (Marutle et al 1999)

p(FPLX:CHRN) negativeCorrelation p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) negativeCorrelation p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 6185c19030
JSON

When the laminar binding distribution of [3H]nicotine, [3H]epibatidine, and [3H]cytisine was measured in AD cortical autopsy tissue, marked reductions were observed relative to control brains (Sihver et al 1999c) (Figure 1)

p(HGNC:CHRNA4) decreases complex(a(CHEBI:cytisine), p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

p(HGNC:CHRNA3) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

Evidence 2128dabe8e
JSON

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b)

p(HGNC:CHRNA4) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Temporal Lobe

p(HGNC:CHRNA7) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

p(HGNC:CHRNA3) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA3) View Subject | View Object

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Annotations
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA4) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence fdf5bd4cce
JSON

This mutation at codon 670/671 on the APP gene on chromosome 21 was discovered in a Swedish family, and the mutation is unique in the sense that it is the only AD mutation that has been shown to alter the APP metabolism, resulting in an overexpression of the amyloid leading to plaque formation (Mullan et al 1992)

act(p(HGNC:APP)) association p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) View Subject | View Object

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p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) association act(p(HGNC:APP)) View Subject | View Object

Appears in Networks:

p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:

Evidence 1fa05ed6a0
JSON

Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999)

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") causesNoChange r(HGNC:CHRNA3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") causesNoChange r(HGNC:CHRNA4) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

r(HGNC:CHRNA7) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 76ff8251be
JSON

The loss in cortical acetylcholinesterase activity was less pronounced in mildly demented AD patients relative to autopsy material and did not strictly correlate with cerebral glucose metabolism impairment (Kuhl et al 1999)

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:ACHE)) View Subject | View Object

Appears in Networks:

Evidence 39fae561c2
JSON

Selective cortical deficits in [11C]nicotine binding are often observed by PET early in the course of the AD disease (Figure 3A)

path(MESH:"Alzheimer Disease") decreases complex(a(CHEBI:nicotine), p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:

Evidence a3286d27f3
JSON

A ligand with a selectivity for the alpha4beta2 nAChRs would be particularly preferable because the alpha4beta2 has been recognized as the predominant subtype that is deficient in AD (for a review, see Sihver et al 2000)

path(MESH:"Alzheimer Disease") decreases a(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

Appears in Networks:

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