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PubMed: 30444369

Title
Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.
Journal
Journal of medicinal chemistry
Volume
None
Issue
None
Pages
None
Date
2018-11-30
Authors
Morsy A | Trippier PC

Evidence f48abfac04
JSON

In mechanistic studies, it was proposed that methylene blue inhibits the Aβ-ABAD interaction and decreases mitochondrial dysfunction by decreasing the expression of ABAD levels, in addition to decreasing Aβ levels.

a(CHEBI:"methylene blue") decreases complex(p(HGNC:APP), p(HGNC:HSD17B10)) View Subject | View Object

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a(CHEBI:"methylene blue") decreases path(HBP:"mitochondrial dysfunction") View Subject | View Object

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a(CHEBI:"methylene blue") decreases p(HGNC:HSD17B10) View Subject | View Object

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a(CHEBI:"methylene blue") decreases a(HBP:"amyloid-beta aggregates") View Subject | View Object

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Evidence b97e8b3689
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Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15 donepezil, 16 rivastigmine 17 and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have had limited effect in improving the cognitive function of AD patients and do not slow the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month

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

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MeSH
Alzheimer Disease

a(CHEBI:donepezil) decreases act(p(FPLX:Cholinesterase)) View Subject | View Object

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

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Alzheimer Disease

a(CHEBI:galanthamine) decreases act(p(FPLX:Cholinesterase)) View Subject | View Object

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

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Alzheimer Disease

a(CHEBI:memantine) decreases act(p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits")) View Subject | View Object

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

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MeSH
Alzheimer Disease

a(CHEBI:rivastigmine) decreases act(p(FPLX:Cholinesterase)) View Subject | View Object

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

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MeSH
Alzheimer Disease

a(CHEBI:tacrine) decreases act(p(FPLX:Cholinesterase)) View Subject | View Object

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Evidence c0139dd827
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Interestingly, during the search for inhibitors of 17β-HSD isoforms for the treatment of estrogen- related diseases, 127 Ayan et.al identified the steroidal compound RM-532-46 (8) as a reversible ABAD inhibitor (IC 50 = 0.55 M).

a(HBP:"RM-532-46") decreases act(p(HGNC:HSD17B10)) View Subject | View Object

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Neurons

Evidence 4297f46bb1
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Mitochondrial dysfunction is the hallmark of Aβ-induced toxicity. 50-52

a(HBP:"amyloid-beta aggregates") increases path(HBP:"mitochondrial dysfunction") View Subject | View Object

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Evidence 35c78c53a8
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Accumulation of Aβ has also been associated with a decrease in the activity of cytochrome c oxidase, the terminal enzyme in the electron transport chain.

a(HBP:"amyloid-beta aggregates") decreases act(p(FPLX:COX)) View Subject | View Object

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Evidence 966034ffef
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Isoforms of CK1 are responsible for tau phosphorylation. 129 The enzyme can modulate the activity of γ-secretase and consequently the production of Aβ.

a(HBP:"amyloid-beta aggregates") association p(HGNC:CSNK1A1) View Subject | View Object

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Neurons

p(HGNC:CSNK1A1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Neurons

p(HGNC:CSNK1A1) regulates act(p(FPLX:"Gamma_secretase")) View Subject | View Object

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Neurons

p(HGNC:CSNK1A1) association a(HBP:"amyloid-beta aggregates") View Subject | View Object

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Neurons

Evidence 36b1ca8a83
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A potent ABAD inhibitor, AG18051 (1), containing a pyrazolo[3,4-d] pyrimidine-4(1H)-thione backbone (IC 50 = 92 nM) has been reported.

a(HBP:AG18051) decreases act(p(HGNC:HSD17B10)) View Subject | View Object

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Neurons

Evidence 77785455c9
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Moreover, it has been shown to ameliorate Aβ-induced toxicity at the cellular level. 7

a(HBP:AG18051) decreases act(a(HBP:"amyloid-beta aggregates")) View Subject | View Object

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Neurons

Evidence 45f8983631
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The frentizole scaffold has been combined with the known monoamine oxidase inhibitor (MAOI) ladostigil to identify a molecule that has a dual effect; inhibiting both ABAD and MAO. A library of synthesized derivatives demonstrated that the most potent inhibitor for MAO (IC 50 = 6.34 µM) lacked ABAD inhibition activity.

a(PUBCHEM:208907) decreases act(p(HGNC:MAOA)) View Subject | View Object

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Neurons

a(PUBCHEM:208907) causesNoChange act(p(HGNC:CSNK1A1)) View Subject | View Object

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Neurons

Evidence 90294a027a
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Frentizole, an FDA approved immunosuppressant drug, was identified as an Aβ-ABAD interaction inhibitor (IC 50 = 200 M) using an ELISA-based screening assay.

a(PUBCHEM:33334) decreases complex(p(HGNC:APP), p(HGNC:HSD17B10)) View Subject | View Object

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Neurons

Evidence 400a40e4a5
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Screening previously synthesized frentizole derivatives for their efficiency to inhibit CK1 activity as well as ABAD, identified compound 13 which possessed an ABAD IC 50 = 1.67 µM, the most potent inhibitor of this chemotype identified to date.

a(PUBCHEM:33334) decreases act(p(HGNC:CSNK1A1)) View Subject | View Object

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Neurons

Evidence 3408149100
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For example, estradiol can reduce the generation of Aβ by altering the metabolism of APP and disrupting it’s trafficking.

a(PUBCHEM:5757) decreases a(HBP:"amyloid-beta aggregates") View Subject | View Object

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Evidence 885ed57f7d
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Moreover, estradiol has been shown to inhibit tau hyperphosphorylation and can also modulate glycogen synthase kinase-3β (GSK-3β) activity, a kinase that is involved in tau phosphorylation. Estradiol deactivates GSK-3β by inducing its phosphorylation, thereafter reducing tau phosphorylation.

a(PUBCHEM:5757) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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a(PUBCHEM:5757) decreases act(p(HGNC:GSK3B)) View Subject | View Object

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a(PUBCHEM:5757) increases p(HGNC:GSK3B, pmod(Ph)) View Subject | View Object

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act(p(HGNC:GSK3B)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Evidence 04e6caa693
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It enhances the expression of anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100 Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101

a(PUBCHEM:5757) increases p(HGNC:BCL2) View Subject | View Object

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Neurons

a(PUBCHEM:5757) increases p(HGNC:BCL2L1) View Subject | View Object

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Neurons

a(PUBCHEM:5757) decreases p(HGNC:BCL2L11) View Subject | View Object

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Neurons

a(PUBCHEM:5757) increases p(HGNC:SOD2) View Subject | View Object

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Neurons

a(PUBCHEM:5757) increases p(FPLX:GPX) View Subject | View Object

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Neurons

p(HGNC:BCL2) decreases bp(GO:"apoptotic process") View Subject | View Object

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Neurons

p(HGNC:BCL2L1) decreases bp(GO:"apoptotic process") View Subject | View Object

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Neurons

p(HGNC:BCL2L11) increases bp(GO:"apoptotic process") View Subject | View Object

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Neurons

Evidence 99101d7ce2
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This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114 which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors, thereby affecting significant aspects of neuronal function such as neurite outgrowth, mitochondrial function, synaptic plasticity and apoptosis. 1

bp(GO:"neuron death") association p(HGNC:SH3GL2) View Subject | View Object

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Neurons

bp(GO:"neuron projection development") association p(HGNC:SH3GL2) View Subject | View Object

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Neurons

bp(GO:"regulation of synaptic plasticity") association p(HGNC:SH3GL2) View Subject | View Object

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Neurons

p(HGNC:SH3GL2) increases act(p(HGNC:MAP3K1)) View Subject | View Object

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Neurons

p(HGNC:SH3GL2) association bp(GO:"neuron projection development") View Subject | View Object

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Neurons

p(HGNC:SH3GL2) association bp(GO:"regulation of synaptic plasticity") View Subject | View Object

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Neurons

p(HGNC:SH3GL2) association bp(GO:"neuron death") View Subject | View Object

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Neurons

Evidence e77f62e242
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Binding of Aβ to ABAD has been implicated in the development of AD, recent studies detected elevated ABAD levels in the regions of the hippocampus and cerebral cortex which are generally affected by AD pathology

p(HGNC:HSD17B10) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Hippocampus

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:HSD17B10) View Subject | View Object

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Cerebral Cortex
MeSH
Hippocampus

Evidence 283fe9cf0d
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The enzyme is also required for the catabolism of isoleucine, in which it catalyzes the conversion of 2-methyl-3-hydroxybutyryl-coA (MHB) to 2-methyl-acetoacetyl-coA. 72

act(p(HGNC:HSD17B10)) increases rxn(reactants(a(PUBCHEM:440326)), products(a(PUBCHEM:193425))) View Subject | View Object

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Evidence ebbe0c5dea
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The enzyme catalyzes the third step of mitochondrial oxidation, converting L -3-hydroxyacyl-CoA in the presence of NAD + to 3-ketoacyl-CoA, NADH, and H + .

act(p(HGNC:HSD17B10)) increases rxn(reactants(a(CHEBI:"NAD(+)"), a(PUBCHEM:9543037)), products(a(CHEBI:"3-oxo-fatty acyl-CoA(4-)"), a(CHEBI:NADH), a(PUBCHEM:1038))) View Subject | View Object

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Evidence 9a687c487c
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The oxidation of 3-adiol to 5-dihydrotestosterone in androgen metabolism is catalyzed by ABAD and it converts 17β-estradiol to estrone in estrogen metabolism.

act(p(HGNC:HSD17B10)) increases rxn(reactants(a(PUBCHEM:15818)), products(a(PUBCHEM:10635))) View Subject | View Object

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act(p(HGNC:HSD17B10)) increases rxn(reactants(a(PUBCHEM:5757)), products(a(PUBCHEM:5870))) View Subject | View Object

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Evidence d289d7faa3
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Moreover, function of ABAD has also been associated with GABA A receptors, as it catalyzes the oxidation of the neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone, both of which are positive modulators of GABA A receptors in the brain.

act(p(HGNC:HSD17B10)) association p(FPLX:GABR) View Subject | View Object

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p(FPLX:GABR) association act(p(HGNC:HSD17B10)) View Subject | View Object

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Evidence 29ff138a6a
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However, it is well established that Aβ binding to ABAD induces a conformational change in the enzyme that prevents the binding of NAD + , preventing the enzyme performing its role in the oxidation of substrates, leading to changes in mitochondrial membrane permeability, which in turn has deleterious effects on mitochondrial enzymes.

complex(p(HGNC:APP), p(HGNC:HSD17B10)) decreases act(p(HGNC:HSD17B10)) View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) decreases complex(a(CHEBI:"NAD(+)"), p(HGNC:HSD17B10)) View Subject | View Object

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Neurons

Evidence 5f8ce84bc0
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Neurons from these animals exhibited increased oxidative stress, increased generation of ROS, DNA fragmentation, neuronal apoptosis, and impairment in learning, compared to single-transgenic mAPP mice.

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases bp(GO:"response to oxidative stress") View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases bp(GO:"apoptotic DNA fragmentation") View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases bp(GO:"neuron death") View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) decreases bp(GO:learning) View Subject | View Object

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Neurons

Evidence 8889b0edfb
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In another study, neurons from Tg mAPP/ABAD mice were shown to exhibit decreased activity of cyclooxygenase (COX) enzyme, spontaneous release of ROS, loss of mitochondrial membrane potential, a decrease in ATP production and release of cytochrome c from mitochondria with subsequent induction of caspase-3-like activity followed by apoptotic cell death.

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) decreases act(p(FPLX:COX)) View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) decreases bp(GO:"regulation of mitochondrial membrane potential") View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) decreases a(CHEBI:ATP) View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases act(p(HGNC:CASP3)) View Subject | View Object

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Neurons

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases bp(GO:"apoptotic process") View Subject | View Object

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Neurons

Evidence 3cbb17b9af
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Genetics have a role to play within AD; patients with a mutation in Amyloid Precursor Protein (APP), which results in overproduction of Aβ, will experience early onset AD. 36 Patients with a mutation in Apolipoprotein E4 (APOE4), which affects the clearance of Aβ, will experience late onset AD.

g(HBP:"APOE e4") increases path(MESH:"Alzheimer Disease") View Subject | View Object

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g(HBP:"APOE e4") decreases deg(p(HGNC:APP)) View Subject | View Object

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g(HGNC:APP, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

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g(HGNC:APP, var("?")) increases p(HGNC:MAPT) View Subject | View Object

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Evidence 051898eb0e
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In addition, several other gene mutations have been discovered such as Presenilin-1 and Presenilin-2 mutations, which increase the risk for developing AD. 38

g(HGNC:PSEN1, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

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g(HGNC:PSEN2, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence 9d650dd678
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The formation of Aβ starts by a transmembrane protein, APP (695 to 770 amino acids in length), which is sequentially cleaved by the aspartate proteases β- and γ-secretase, that leads to the formation of Aβ peptide (1-42) and a degenerated C-terminus.

p(FPLX:"Gamma_secretase") increases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta polypeptide 42"), p(HBP:"APP C-terminally truncated carboxyl-terminal fragments"))) View Subject | View Object

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p(HGNC:BACE1) increases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta polypeptide 42"), p(HBP:"APP C-terminally truncated carboxyl-terminal fragments"))) View Subject | View Object

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Evidence 841b481d3d
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Inactivation of Prdx-2 is controlled by a kinase that has been shown to be elevated in AD, CDK5, 107, 108 which phosphorylates Thr 89 and results in deactivation of Prdx-2.

p(HGNC:CDK5) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Neurons

p(HGNC:CDK5) increases p(HGNC:PRDX2, pmod(Ph, Thr, 89)) View Subject | View Object

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Neurons

p(HGNC:PRDX2, pmod(Ph, Thr, 89)) decreases act(p(HGNC:PRDX2)) View Subject | View Object

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Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:CDK5) View Subject | View Object

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Neurons

Evidence f8d6f60c1e
JSON

The first, peroxiredoxin-2 (Prdx-2), functions as an antioxidant and has been shown to be inactivated in AD.

act(p(HGNC:PRDX2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:PRDX2)) View Subject | View Object

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Neurons

Evidence 231e26c348
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In transgenic AD mice and the post-mortem human brain of AD patients, the expression of Prdx-2 is shown to be elevated, due to the attempted protection of neurons from Aβ-induced toxicity.

p(HGNC:PRDX2) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:PRDX2) View Subject | View Object

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Neurons

Evidence ab56890fd0
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The second ABAD-related protein, endophilin-1 (Ep-1), is a member of a family of proteins that are responsible for synaptic vesicle endocytosis, mitochondrial function, and receptor trafficking. 110 This family of proteins has been implicated in a number of neurodegenerative diseases, 111 including in AD where it is overexpressed

p(HGNC:SH3GL2) increases bp(GO:"synaptic vesicle endocytosis") View Subject | View Object

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Neurons

p(HGNC:SH3GL2) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SH3GL2) View Subject | View Object

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MeSH
Neurons

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