Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Июнь 8, 2018

Abstract Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood–brain barrier, and reduce beta-amyloid tau pathology animal models of Alzheimer’s disease. Here, we used barrier five patients early moderate disease a phase I safety trial. In all patients, within target volume was safely, reversibly, repeatedly opened. Opening did not result serious clinical or radiographic adverse events, as well no clinically significant worsening on cognitive scores at three months compared baseline. Beta-amyloid levels were measured before treatment using [ 18 F]-florbetaben PET confirm amyloid deposition site. Exploratory analysis suggested group-wise changes post-sonication. The results this feasibility study support continued investigation potential novel delivery strategy for

Язык: Английский

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The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

Journal of Alzheimer s Disease, Год журнала: 2018, Номер 64(s1), С. S567 - S610

Опубликована: Июнь 12, 2018

The amyloid-␤ oligomer (A␤O) hypothesis was introduced in 1998.It proposed that the brain damage leading to Alzheimer's disease (AD) instigated by soluble, ligand-like A␤Os.This based on discovery fibril-free synthetic preparations of A␤Os were potent CNS neurotoxins rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998).The mechanism attributed disrupted signaling involving tyrosine-protein kinase Fyn, mediated an unknown toxin receptor.Over 4,000 articles concerning have been published since then, including more than 400 reviews.A␤Os shown accumulate AD-dependent manner human and animal model tissue experimentally, impair learning memory instigate major facets AD neuropathology, tau pathology, synapse deterioration loss, inflammation, oxidative damage.As reviewed Hayden Teplow 2013, A␤O "has all but supplanted amyloid cascade."Despite emerging understanding role played pathogenesis, not yet received clinical attention given plaques, which at core attempts therapeutics diagnostics are no longer regarded as most pathogenic form A␤.However, if momentum research continues, particularly efforts elucidate key aspects structure, a clear path successful modifying therapy can be envisioned.Ensuring lessons learned from recent, late-stage failures applied appropriately throughout therapeutic development will further enable likelihood near-term.

Язык: Английский

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Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Год журнала: 2021, Номер 121(4), С. 2545 - 2647

Опубликована: Фев. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Язык: Английский

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A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease

Nature Neuroscience, Год журнала: 2018, Номер 21(7), С. 941 - 951

Опубликована: Июнь 27, 2018

Язык: Английский

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Amyloid-β-independent regulators of tau pathology in Alzheimer disease

Nature reviews. Neuroscience, Год журнала: 2019, Номер 21(1), С. 21 - 35

Опубликована: Ноя. 28, 2019

Язык: Английский

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A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Nature Medicine, Год журнала: 2021, Номер 27(7), С. 1187 - 1196

Опубликована: Июнь 21, 2021

Язык: Английский

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Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

Molecules, Год журнала: 2017, Номер 22(8), С. 1287 - 1287

Опубликована: Авг. 2, 2017

P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer’s disease (AD) characterized by the presence of amyloid plaques and neurofibrillary tangles in brain, as well neurodegeneration, there no known cure. Recent studies on underlying biology AD cellular animal models have indicated that p38 MAPK capable orchestrating diverse events related to AD, such tau phosphorylation, neurotoxicity, neuroinflammation synaptic dysfunction. Thus, inhibition considered promising strategy treatment AD. In this review, we summarize recent advances targeting potential envision possibilities inhibitors fundamental therapeutics

Язык: Английский

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Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Nature reviews. Neuroscience, Год журнала: 2019, Номер 20(2), С. 94 - 108

Опубликована: Янв. 14, 2019

Язык: Английский

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Zebrafish: an emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery

Cell Death Discovery, Год журнала: 2018, Номер 4(1)

Опубликована: Окт. 3, 2018

Zebrafish (Danio rerio) is emerging as an increasingly successful model for translational research on human neurological disorders. In this review, we appraise the high degree of and behavioural resemblance zebrafish with humans. It highly validated a powerful vertebrate investigating neurodegenerative diseases. The neuroanatomic neurochemical pathways brain exhibit profound brain. Physiological, emotional social pattern similarities between them have also been well established. Interestingly, models used successfully to simulate pathology Alzheimer's disease (AD) Tauopathy. Their relatively simple nervous system optical transparency embryos permit real-time imaging. Here, further elaborate use recent imaging techniques obtain vital insights into neurodegeneration that occurs in AD. adeptly suitable Ca2+ imaging, which provides better understanding neuronal activity axonal dystrophy non-invasive manner. Three-dimensional rapidly evolving technique, allows visualisation whole organism vivo functional neurophysiological analysis condition. Suitability high-throughput screening similarity humans makes excellent neurospecific compounds. Thus, can be pivotal bridging gap from bench bedside. This fish becoming understand AD scope investigation neurodevelopment neurodegeneration, promises exciting opportunities future.

Язык: Английский

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Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease

Neural Regeneration Research, Год журнала: 2021, Номер 17(8), С. 1666 - 1666

Опубликована: Дек. 10, 2021

Alzheimer's disease is a neurodegenerative that accounts for most of the 50-million dementia cases worldwide in 2018. A large amount evidence supports amyloid cascade hypothesis, which states amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation form neurofibrillary tangles, these aggregates lead to inflammation, synaptic impairment, neuronal loss, thus cognitive decline behavioral abnormalities. The poor correlation found between plaques, have led scientific community question whether actually triggering neurodegeneration disease. occurrence tangles better correlates loss clinical symptoms and, although may initiate events, impairment likely effector molecule neurodegeneration. Recently, it has been shown cooperatively work impair transcription genes involved function more importantly, downregulation partially reverses transcriptional perturbations. Despite mounting points an interplay tau, some factors could independently affect both pathologies. Thus, dual pathway there are common upstream causing abnormalities proposed. Among others, immune system seems be strongly Other factors, as apolipoprotein E ε4 isoform suggested act link hyperphosphorylation. Interestingly, amyloid-beta-immunotherapy reduces not only but also levels animal models trials. Likewise, tau-immunotherapy levels. even though immunotherapy advanced than tau-immunotherapy, combined tau-directed therapies at early stages recently proposed strategy stop progression

Язык: Английский

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