Tau protein and tau aggregation inhibitors

Bulic, Bruno; Pickhardt, Marcus; Mandelkow, Eva‐Maria; Mandelkow, Eckhard

doi:10.1016/j.neuropharm.2010.01.016

Cited by 162 publications

(127 citation statements)

References 152 publications

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“…Cite this article as Cold Spring Harb Perspect Med 2012;2:a006247 www.perspectivesinmedicine.org Bulic et al 2010;. One recent example is the design of a capping peptide blocking the elongation of PHFs (Sievers et al 2011).…”

Section: Tau Protein In Neurofibrillary Degenerationmentioning

confidence: 99%

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow

2012

Cold Spring Harbor Perspectives in Medicine

705

636

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Tau represents the subunit protein of one of the major hallmarks of Alzheimer disease (AD), the neurofibrillary tangles, and is therefore of major interest as an indicator of disease mechanisms. Many of the unusual properties of Tau can be explained by its nature as a natively unfolded protein. Examples are the large number of structural conformations and biochemical modifications ( phosphorylation, proteolysis, glycosylation, and others), the multitude of interaction partners (mainly microtubules, but also other cytoskeletal proteins, kinases, and phosphatases, motor proteins, chaperones, and membrane proteins). The pathological aggregation of Tau is counterintuitive, given its high solubility, but can be rationalized by short hydrophobic motifs forming b structures. The aggregation of Tau is toxic in cell and animal models, but can be reversed by suppressing expression or by aggregation inhibitors. This review summarizes some of the structural, biochemical, and cell biological properties of Tau and Tau fibers. Further aspects of Tau as a diagnostic marker and therapeutic target, its involvement in other Tau-based diseases, and its histopathology are covered by other chapters in this volume.

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Section: Tau Protein In Neurofibrillary Degenerationmentioning

confidence: 99%

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow

2012

Cold Spring Harbor Perspectives in Medicine

705

636

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“…12 In this respect, compound ITH12246 could be considered as a wide spectrum neuroprotectant, a profile that is interesting taking into account the multifactorial nature of neurodegenerative diseases that, however, currently do not possess a huge battery of therapeutic strategies to slow down or counteract the disease. This is more dramatic in the case of AD, as there are no optimal medicines to treat AD patients, although the scientific community is tirelessly looking for new promising drugs and compromised targets, focusing mainly on the best-known physiopathological markers, that is Aβ 68 or aggregated τ protein, 69 as well as the so-called cholinergic hypothesis; 70 unfortunately, all of these approaches have failed. 71 As mentioned in the introduction section, stroke does not possess efficient medicines, too.…”

Section: ■ Conclusionmentioning

confidence: 99%

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

Lorrio

Romero

González‐Lafuente

et al. 2013

ACS Chem. Neurosci.

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ITH12246 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b] [1,8]naphthyridine-3-carboxylate) is a 1,8-naphthyridine described to feature an interesting neuroprotective profile in in vitro models of Alzheimer's disease. These effects were proposed to be due in part to a regulatory action on protein phosphatase 2A inhibition, as it prevented binding of its inhibitor okadaic acid. We decided to investigate the pharmacological properties of ITH12246, evaluating its ability to counteract the memory impairment evoked by scopolamine, a muscarinic antagonist described to promote memory loss, as well as to reduce the infarct volume in mice suffering phototrombosis. Prior to conducting these experiments, we confirmed its in vitro neuroprotective activity against both oxidative stress and Ca 2+ overload-derived excitotoxicity, using SH-SY5Y neuroblastoma cells and rat hippocampal slices. Using a predictive model of blood-brain barrier crossing, it seems that the passage of ITH12246 is not hindered. Its potential hepatotoxicity was observed only at very high concentrations, from 0.1 mM. ITH12246, at the concentration of 10 mg/kg i.p., was able to improve the memory index of mice treated with scopolamine, from 0.22 to 0.35, in a similar fashion to the well-known Alzheimer's disease drug galantamine 2.5 mg/kg. On the other hand, ITH12246, at the concentration of 2.5 mg/kg, reduced the phototrombosis-triggered infarct volume by 67%. In the same experimental conditions, 15 mg/kg melatonin, used as control standard, reduced the infarct volume by 30%. All of these findings allow us to consider ITH12246 as a new potential drug for the treatment of neurodegenerative diseases, which would act as a multifactorial neuroprotectant.

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“…Despite these findings, AD therapeutics has scarcely focused on the clinical development of cell Ca 2+ -regulating agents, 16 except for NMDA-sensitive glutamate receptor blockers, 17 even when new biological targets modulating [Ca 2+ ] c , such as the above-mentioned CALHM-1 channel, have been related to AD. Nevertheless, the search of optimal medicines to counteract the progression of AD, 18 by means of targeting well-known physiopathological markers, that is, Aβ 19 or aggregated tau (τ) protein, 20 as well as the so-called cholinergic hypothesis, 21 has been disappointing. 22 During the past decade, our research group has been studying new voltage-dependent Ca 2+ channel (VDCC) ligands as new [Ca 2+ ] regulators for the treatment of AD.…”

Section: + Concentrations ([Camentioning

confidence: 99%

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

González‐Lafuente

Egea

León

et al. 2012

ACS Chem. Neurosci.

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Benzothiazepine CGP37157 is widely used as tool to explore the role of mitochondria in cell Ca 2+ handling, by its blocking effect of the mitochondria Na + /Ca 2+ exchanger. Recently, CGP37157 has shown to exhibit neuroprotective properties. In the trend to improve its neuroprotection profile, we have synthesized ITH12505, an isosteric analogue having a methyl instead of chlorine at C2′ of the phenyl ring. ITH12505 has exerted neuroprotective properties similar to CGP37157 in chromaffin cells and hippocampal slices stressed with veratridine. Also, both compounds afforded neuroprotection in hippocampal slices stressed with glutamate. However, while ITH12505 elicited protection in SH-SY5Y cells stressed with oligomycin A/rotenone, CGP37157 was ineffective. In hippocampal slices subjected to oxygen/glucose deprivation plus reoxygenation, ITH12505 offered protection at 3−30 μM, while CGP37157 only protected at 30 μM. Both compounds caused blockade of Ca 2+ channels in high K + -depolarized SH-SY5Y cells. An in vitro experiment for assaying central nervous system penetration (PAMPA-BBB; parallel artificial membrane permeability assay for blood-brain barrier) revealed that both compounds could cross the blood−brain barrier, thus reaching their biological targets in the central nervous system. In conclusion, by causing a mild isosteric replacement in the benzothiazepine CGP37157, we have obtained ITH12505, with improved neuroprotective properties. These findings may inspire the design and synthesis of new benzothiazepines targeting mitochondrial Na + /Ca 2+ exchanger and L-type voltage-dependent Ca 2+ channels, having antioxidant properties.

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Tau protein and tau aggregation inhibitors

Cited by 162 publications

References 152 publications

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

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