Alzheimer’s disease hypothesis and related therapies

Translational Neurodegeneration, Год журнала: 2018, Номер 7(1)

Опубликована: Янв. 24, 2018

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause for dementia. There are many hypotheses about AD, including abnormal deposit of amyloid β (Aβ) protein in extracellular spaces neurons, formation twisted fibers tau proteins inside cholinergic neuron damage, inflammation, oxidative stress, etc., anti-AD drugs based on these have been developed. In this review, we will discuss existing emerging hypothesis related therapies.

Язык: Английский

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Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

Nature Reviews Drug Discovery, Год журнала: 2018, Номер 17(9), С. 660 - 688

Опубликована: Авг. 17, 2018

Язык: Английский

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The blood-brain barrier: Physiology and strategies for drug delivery

Advanced Drug Delivery Reviews, Год журнала: 2019, Номер 165-166, С. 1 - 14

Опубликована: Ноя. 29, 2019

Язык: Английский

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Rodent models for Alzheimer disease

Nature reviews. Neuroscience, Год журнала: 2018, Номер 19(10), С. 583 - 598

Опубликована: Сен. 7, 2018

Язык: Английский

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Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway

European Journal of Medicinal Chemistry, Год журнала: 2018, Номер 146, С. 251 - 259

Опубликована: Фев. 1, 2018

Язык: Английский

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A walk through tau therapeutic strategies

Acta Neuropathologica Communications, Год журнала: 2019, Номер 7(1)

Опубликована: Фев. 15, 2019

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease related human tauopathies. There is a growing body evidence indicating that pathological tau species can travel from cell to spread pathology through brain. Throughout last decade, physiological have become attractive targets for AD therapies. Several therapeutic approaches been proposed, including inhibition protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, aggregation, active passive immunotherapies, silencing by antisense oligonucleotides. New therapeutics, across board, demonstrated ability prevent reduce lesions improve either cognitive motor impairment in variety animal models developing neurofibrillary pathology. The most advanced strategy treatment tauopathies remains immunotherapy, which has already reached stage drug development. vaccines humanised antibodies target intracellular extracellular spaces. Some them recognise amino-terminus carboxy-terminus, while others display binding abilities proline-rich area microtubule domains. main foci existing trials are on disease, progressive supranuclear palsy non-fluent primary aphasia. therapy offers new hope many fatal brain disorders. First efficacy data will be available end this decade.

Язык: Английский

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Medicinal Research Reviews, Год журнала: 2019, Номер 40(1), С. 339 - 384

Опубликована: Июль 26, 2019

Abstract Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches AD inhibition β‐site APP cleaving enzyme‐1 (BACE1), which involved in rate‐limiting step cleavage process amyloid precursor protein (APP) leading to generation neurotoxic β (Aβ) after γ‐secretase completes its function. The produced insoluble Aβ aggregates lead plaques deposition and neurodegeneration. BACE1 is, therefore, one attractive targets for treatment AD. This approach led development potent inhibitors, many were advanced late stages clinical trials. Nonetheless, high failure rate drug candidates targeting brought forefront need finding new uncover mystery behind In this review, we aim discuss most promising classes inhibitors a description analysis their pharmacodynamic pharmacokinetic parameters, more focus on that reached trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, CNP520. addition, manuscript discusses safety concerns insignificant physiological effects, highlighted successful inhibitors. Furthermore, review demonstrates increasing evidence despite tremendous efforts results conceived latest studies suggest use treating should be reconsidered. Finally, sheds light alternative options

Язык: Английский

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Molecular Pathogenesis of the Tauopathies

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2018, Номер 14(1), С. 239 - 261

Опубликована: Окт. 25, 2018

The tauopathies constitute a group of diseases that have Tau inclusions in neurons or glia as their common denominator. In this review, we describe the biochemical and histological differences pathology are characteristic spectrum frontotemporal lobar degeneration primary Alzheimer's disease secondary tauopathy, well commonalities between familial sporadic forms. Furthermore, discuss selected advances transgenic animal models delineating different pathomechanisms Tau.

Язык: Английский

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Lysine/RNA-interactions drive and regulate biomolecular condensation

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Июль 2, 2019

Abstract Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound are directly connected the amino acid content disordered protein regions. Lysine plays an important role in cellular function, but little is known about its condensation. Here we show that disorder abundant protein/RNA granules lysine enriched regions proteins P-bodies compared entire human proteome. Lysine-rich polypeptides phase separate into lysine/RNA-coacervates more dynamic differ at level from arginine/RNA-coacervates. Consistent with ability drive separation, lysine-rich variants Alzheimer’s disease-linked tau undergo coacervation RNA vitro bind stress cells. Acetylation reverses liquid–liquid separation reduces colocalization granules. Our study establishes as regulator

Язык: Английский

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Disease‐associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria

The EMBO Journal, Год журнала: 2018, Номер 38(3)

Опубликована: Дек. 11, 2018

Accumulation of the protein tau characterises Alzheimer's disease and other tauopathies, including familial forms frontotemporal dementia (FTD) that carry pathogenic mutations. Another hallmark feature these diseases is accumulation dysfunctional mitochondria. Although disease-associated known to impair several aspects mitochondrial function, it still unclear whether also directly impinges on quality control, specifically Parkin-dependent mitophagy. Using mito-QC mitophagy reporter, we found both human wild-type (hTau) FTD mutant (hP301L) inhibited in neuroblastoma cells, by reducing translocation Parkin. In Caenorhabditis elegans nervous system, hTau expression reduced mitophagy, whereas hP301L completely it. These effects were not due changes membrane potential or cytoskeleton, as impaired Parkin recruitment defective mitochondria sequestering cytosol. This sequestration was mediated aberrant interactions with projection domain tau. As are neurodegenerative conditions, data suggest a vicious cycle, inhibiting degradation damaged

Язык: Английский

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