A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model

Autor:	John Q. Trojanowski, Virginia M.-Y. Lee, Yuemang Yao, Kurt R. Brunden, Carlo Ballatore, Pyry Koivula, Michael J. James, Amos B. Smith, Killian Oukoloff, Anne-Sophie Cornec, Bin Zhang
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	0301 basic medicine Aging Neurodegenerative lcsh:Geriatrics Alzheimer's Disease Axonal Transport Microtubules lcsh:RC346-429 Blood cell Mice 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Alzheimer's Disease Related Dementias (ADRD) Neurons biology Chemistry Brain 3. Good health Vinblastine Cell biology Frontotemporal Dementia (FTD) Tauopathy medicine.anatomical_structure Tauopathies Neurological Therapeutic Alzheimer’s disease medicine.drug Research Article Genetically modified mouse Tau protein Clinical Sciences tau Proteins Microtubule 03 medical and health sciences Cellular and Molecular Neuroscience Rare Diseases Alzheimer Disease medicine Acquired Cognitive Impairment Genetics Animals Humans Molecular Biology lcsh:Neurology. Diseases of the nervous system Neurology & Neurosurgery Animal Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Triazoles medicine.disease Molecular medicine Axons Barnes maze Brain Disorders Disease Models Animal lcsh:RC952-954.6 030104 developmental biology Disease Models Axoplasmic transport biology.protein Quinazolines Dementia Neurology (clinical) 030217 neurology & neurosurgery
Zdroj:	Molecular Neurodegeneration, Vol 13, Iss 1, Pp 1-15 (2018) Molecular Neurodegeneration Molecular neurodegeneration, vol 13, iss 1
ISSN:	1750-1326
DOI:	10.1186/s13024-018-0291-3
Popis:	Background Alzheimer’s disease (AD) and related tauopathies are neurodegenerative diseases that are characterized by the presence of insoluble inclusions of the protein tau within brain neurons and often glia. Tau is normally found associated with axonal microtubules (MTs) in the brain, and in tauopathies this MT binding is diminished due to tau hyperphosphorylation. As MTs play a critical role in the movement of cellular constituents within neurons via axonal transport, it is likely that the dissociation of tau from MTs alters MT structure and axonal transport, and there is evidence of this in tauopathy mouse models as well as in AD brain. We previously demonstrated that different natural products which stabilize MTs by interacting with β-tubulin at the taxane binding site provide significant benefit in transgenic mouse models of tauopathy. More recently, we have reported on a series of MT-stabilizing triazolopyrimidines (TPDs), which interact with β-tubulin at the vinblastine binding site, that exhibit favorable properties including brain penetration and oral bioavailability. Here, we have examined a prototype TPD example, CNDR-51657, in a secondary prevention study utilizing aged tau transgenic mice. Methods 9-Month old female PS19 mice with a low amount of existing tau pathology received twice-weekly administration of vehicle, or 3 or 10 mg/kg of CNDR-51657, for 3 months. Mice were examined in the Barnes maze at the end of the dosing period, and brain tissue and optic nerves were examined immunohistochemically or biochemically for changes in MT density, axonal dystrophy, and tau pathology. Mice were also assessed for changes in organ weights and blood cell numbers. Results CNDR-51657 caused a significant amelioration of the MT deficit and axonal dystrophy observed in vehicle-treated aged PS19 mice. Moreover, PS19 mice receiving CNDR-51657 had significantly lower tau pathology, with a trend toward improved Barnes maze performance. Importantly, no adverse effects were observed in the compound-treated mice, including no change in white blood cell counts as is often observed in cancer patients receiving high doses of MT-stabilizing drugs. Conclusions A brain-penetrant MT-stabilizing TPD can safely correct MT and axonal deficits in an established mouse model of tauopathy, resulting in reduced tau pathology. Electronic supplementary material The online version of this article (10.1186/s13024-018-0291-3) contains supplementary material, which is available to authorized users.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::24a4ec642d121eacc65cb286398365ab http://link.springer.com/article/10.1186/s13024-018-0291-3 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.