PubMed: 30444369

Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.
Journal of medicinal chemistry
Morsy A | Trippier PC

Evidence f48abfac04

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.

Evidence b97e8b3689

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

Evidence c0139dd827

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

Evidence 4297f46bb1

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

Evidence 35c78c53a8

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.

Evidence 966034ffef

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

Evidence 36b1ca8a83

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

Evidence 77785455c9

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

Evidence 45f8983631

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.

Evidence 90294a027a

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

Evidence 400a40e4a5

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.

Evidence 3408149100

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

Evidence 885ed57f7d

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.

Evidence 04e6caa693

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

Evidence 99101d7ce2

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

Evidence e77f62e242

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

Evidence 283fe9cf0d

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

Evidence ebbe0c5dea

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 + .

Evidence 9a687c487c

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.

Evidence d289d7faa3

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.

Evidence 29ff138a6a

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.

Evidence 5f8ce84bc0

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.

Evidence 8889b0edfb

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.

Evidence 3cbb17b9af

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.

Evidence 051898eb0e

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

Evidence 9d650dd678

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.

Evidence 841b481d3d

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.

Evidence f8d6f60c1e

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

Evidence 231e26c348

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.

Evidence ab56890fd0

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


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