Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease DOI
Yujing Liu, Yun Tan,

Guopan Cheng

et al.

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(19)

Published: Feb. 23, 2024

Abstract The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction reactive oxygen species overproduction. However, the treatment AD remains challenging owning to hindrance caused by blood–brain barrier (BBB) complex pathology AD. Nasal delivery represents an effective means circumventing BBB delivering drugs brain. In this study, black phosphorus (BP) used as drug carrier, well antioxidant, loaded with aggregation inhibitor, methylene blue (MB), obtain BP‐MB. For intranasal (IN) delivery, thermosensitive hydrogel fabricated cross‐linking carboxymethyl chitosan aldehyde Pluronic F127 (F127‐CHO) micelles. BP‐MB nanocomposite incorporated into BP‐MB@Gel. BP‐MB@Gel could be injected intranasally, providing high nasal mucosal retention controlled release. After IN administration, continuously released delivered brain, exerting synergistic therapeutic effects suppressing neuropathology, restoring function, alleviating neuroinflammation, thus inducing cognitive improvements mouse models These findings highlight potential strategy for brain‐targeted management pathologies

Language: Английский

Alzheimer’s disease hypothesis and related therapies DOI Creative Commons

Xiaoguang Du,

Xinyi Wang, Meiyu Geng

et al.

Translational Neurodegeneration, Journal Year: 2018, Volume and Issue: 7(1)

Published: Jan. 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.

Language: Английский

Citations

540
Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing DOI
Barry Boland, Wen H. Yu, Olga Corti

et al.

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(9), P. 660 - 688

Published: Aug. 17, 2018

Language: Английский

Citations

471
The blood-brain barrier: Physiology and strategies for drug delivery DOI
Rucha Pandit, Liyu Chen, Jürgen Götz

et al.

Advanced Drug Delivery Reviews, Journal Year: 2019, Volume and Issue: 165-166, P. 1 - 14

Published: Nov. 29, 2019

Language: Английский

Citations

459
Rodent models for Alzheimer disease DOI
Jürgen Götz, Liviu‐Gabriel Bodea, Michel Goedert

et al.

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(10), P. 583 - 598

Published: Sept. 7, 2018

Language: Английский

Citations

305
Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway DOI
Mengchen Lu, Tian Liu,

Qiong Jiao

et al.

European Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 146, P. 251 - 259

Published: Feb. 1, 2018

Language: Английский

Citations

250
A walk through tau therapeutic strategies DOI Creative Commons
Santosh Jadhav, Jesús Ávila, Michael Schöll

et al.

Acta Neuropathologica Communications, Journal Year: 2019, Volume and Issue: 7(1)

Published: Feb. 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.

Language: Английский

Citations

248
BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease DOI Open Access

Nour M. Moussa‐Pacha,

Shifaa M. Abdin, Hany A. Omar

et al.

Medicinal Research Reviews, Journal Year: 2019, Volume and Issue: 40(1), P. 339 - 384

Published: July 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

Language: Английский

Citations

247
Molecular Pathogenesis of the Tauopathies DOI
Jürgen Götz, Glenda M. Halliday, Rebecca M. Nisbet

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2018, Volume and Issue: 14(1), P. 239 - 261

Published: Oct. 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.

Language: Английский

Citations

228
Lysine/RNA-interactions drive and regulate biomolecular condensation DOI Creative Commons
Tina Ukmar,

Saskia Hutten,

Matthew P. Grieshop

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: July 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

Language: Английский

Citations

221
Disease‐associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria DOI Creative Commons
Nadia Cummins,

Andrea Tweedie,

Steven Zuryn

et al.

The EMBO Journal, Journal Year: 2018, Volume and Issue: 38(3)

Published: Dec. 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

Language: Английский

Citations

214