Role of neuroinflammation in neurodegeneration development

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июль 12, 2023

Abstract Studies in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis, Huntington’s so on, have suggested that inflammation is not only a result of neurodegeneration but also crucial player this process. Protein aggregates which are very common pathological phenomenon can induce neuroinflammation further aggravates protein aggregation neurodegeneration. Actually, even happens earlier than aggregation. Neuroinflammation induced by genetic variations CNS cells or peripheral immune may deposition some susceptible population. Numerous signaling pathways range been to be involved the pathogenesis neurodegeneration, although they still far from being completely understood. Due limited success traditional treatment methods, blocking enhancing inflammatory considered promising strategies for therapy many them got exciting results animal models clinical trials. Some them, few, approved FDA usage. Here we comprehensively review factors affecting major pathogenicity sclerosis. We summarize current strategies, both clinic, diseases.

Язык: Английский

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Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

Frontiers in Aging Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Апрель 12, 2022

Alzheimer's disease (AD) is the most prevalent form of age-related dementia in world, and its main pathological features consist amyloid-β (Aβ) plaque deposits neurofibrillary tangles formed by hyperphosphorylated tau protein. So far, only a few AD treatments approved have been applied clinic, but effects these drugs are limited for partial symptomatic relief to patients with unable alter progression. Later, all efforts targeting pathogenic factors were unsuccessful over past decades, which suggested that pathogenesis complex. Recently, disease-modifying therapies (DMTs) can change underlying pathophysiology AD, anti-Aβ monoclonal antibodies (mabs) (e.g., aducanumab, bapineuzumab, gantenerumab, solanezumab, lecanemab) developed successively conducted clinical trials based on theory systemic failure cell-mediated Aβ clearance contributes occurrence In review, we summarized recent studies therapeutic trial results mabs AD. Specifically, focused discussion impact aducanumab lecanemab pathology profiles. The review provides possible evidence applying immunotherapy analyzes lessons learned from order further study adverse

Язык: Английский

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Microglia Phenotypes in Aging and Neurodegenerative Diseases

Cells, Год журнала: 2022, Номер 11(13), С. 2091 - 2091

Опубликована: Июнь 30, 2022

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays fundamental role in mediating the onset progression disease. Microglia, which function as first-line immune guardians central nervous system (CNS), are drivers neuroinflammation. Numerous human postmortem studies vivo imaging analyses have shown chronically activated microglia patients with various acute chronic neuropathological diseases. While microglial activation common feature NDs, exact pathological states complex often contradictory. However, there consensus that play biphasic conditions, detrimental protective phenotypes, overall response different phenotypes depends on nature duration inflammatory insult, well stage disease development. This review provides comprehensive overview current research responses health, aging, special emphasis heterogeneous phenotypic such hemorrhagic stroke (HS), Alzheimer's (AD), Parkinson's (PD). The primary focus translational preclinical animal models bulk/single-cell transcriptome samples. Additionally, this covers key receptors signaling pathways potential therapeutic targets to regulate during aging NDs. age-, sex-, species-specific differences will be briefly reviewed.

Язык: Английский

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Aducanumab: evidence from clinical trial data and controversies

Drugs in Context, Год журнала: 2021, Номер 10, С. 1 - 9

Опубликована: Сен. 30, 2021

Alzheimer's disease (AD) is the most common cause for dementia worldwide. Until recently, all approved treatments AD were symptomatic and not modifying. On 7 June 2021, US FDA aducanumab, a human IgG1 anti-Aβ monoclonal antibody selective Aβ aggregates, as first disease-modifying treatment AD. Aducanumab in United States of mild cognitive impairment or mild-dementia stage In this Editorial, we review trial data aducanumab controversies that its approval has generated.

Язык: Английский

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Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Clinical Interventions in Aging, Год журнала: 2022, Номер Volume 17, С. 797 - 810

Опубликована: Май 1, 2022

Abstract: Aducanumab is a monoclonal antibody selective for amyloid β (Aβ) aggregates. In June 2021, aducanumab became the first drug underlying pathophysiology of Alzheimer's disease (AD) approved by US Food and Drug Administration (FDA), under accelerated approval pathway. The decision was based on ability to remove Aβ plaques, without any evidence that clearance correlated with less cognitive or functional decline. This has generated considerable debate in scientific community, especially because results from two Phase 3 trials, EMERGE ENGAGE, were divergent and, even after post hoc analysis, data insufficient prove efficacy. Moreover, some researchers think this will be an obstacle progress also demonstrated concerns about cost its safety profile. European Medicines Agency's rejection December 2021 just brought more controversy over FDA's decision. Now, Biogen designing required confirmatory study, named ENVISION, which should complete 2026. Despite controversy, showed affect downstream tau pathology, could open doors combination therapy approach AD (anti-tau anti-amyloid drug). review summarizes clinical development until regulatory agencies' decisions, available trials AD. Keywords: anti-Aβ antibody, ARIA, Agency, Administration, protein

Язык: Английский

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Ultrasound-mediated blood–brain barrier opening: An effective drug delivery system for theranostics of brain diseases

Advanced Drug Delivery Reviews, Год журнала: 2022, Номер 190, С. 114539 - 114539

Опубликована: Сен. 15, 2022

Язык: Английский

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Early diagnosis of Alzheimer's disease based on deep learning: A systematic review

Computers in Biology and Medicine, Год журнала: 2022, Номер 146, С. 105634 - 105634

Опубликована: Май 17, 2022

Язык: Английский

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Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis

The Annals of Family Medicine, Год журнала: 2024, Номер 22(1), С. 50 - 62

Опубликована: Янв. 1, 2024

PURPOSE

We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia.

METHODS

searched PubMed, Cochrane CENTRAL, 5 trial registries, as well the reference lists identified studies. included randomized controlled trials comparing antibody placebo at dose consistent that used phase 3 or for Food Drug Administration approval. Studies had report least 1 relevant benefit harm. Data were extracted independently by 2 researchers random effects meta-analysis. Changes cognitive functional scales compared between groups, each difference was assessed determine if it met minimal important (MCID).

RESULTS

19 publications 23,202 total participants evaluated 8 anti-amyloid antibodies. There small improvements over Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 -14 score (standardized mean = −0.07; 95% CI, −0.10 −0.04), Mini Mental State Examination (0.32 points; 0.13 0.50), Clinical Dementia Rating-Sum Boxes scale (mean =−0.18 −0.34 −0.03), combined scores 0.09; 0.05 0.13). None changes, including those lecanemab, aducanumab, donanemab, exceeded MCID. Harms significantly increased risks amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] 10.29; number needed harm [NNH] 9), ARIA-hemorrhage (RR 1.74; NNH 13), symptomatic ARIA-edema 24.3; 86).

CONCLUSIONS

Although provide on dementia, these are far below MCID outcome accompanied harms.

Язык: Английский

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Multi Targeted Therapy for Alzheimer’s Disease by Guanidinium-Modified Calixarene and Cyclodextrin Co-Assembly Loaded with Insulin

ACS Nano, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 5, 2024

Amyloid-β (Aβ) is considered a primary therapeutic target for Alzheimer's disease (AD). However, just eliminating Aβ in patients with AD has exhibited restricted clinical efficacy, possibly failing to address the metabolic abnormalities caused by AD, such as insulin resistance. To this concern, our research employed two types of macrocyclic amphiphiles, guanidinium-modified calixarene and cyclodextrin coassembly (GCD), delivery systems insulin. This approach aimed tackle dysregulation characteristic an innovative manner exploring beyond conventional strategy removal. As result, GCD could effectively improve plaque deposition The also reduce abnormal neuronal apoptosis synaptic damage cognitive impairment 5xFAD mice. Therefore, shows promise viable option AD.

Язык: Английский

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Pharmacological enhancement of slow-wave activity at an early disease stage improves cognition and reduces amyloid pathology in a mouse model of Alzheimer’s disease

Frontiers in Aging Neuroscience, Год журнала: 2025, Номер 16

Опубликована: Янв. 3, 2025

Improving sleep in murine Alzheimer's disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions, regarding reduction pathological hallmarks and related cognitive performance, remains poorly characterized. Here, we enhanced slow-wave activity (SWA) during via sodium oxybate (SO) oral administration 2 weeks at early (6 months old) or moderately late (11 stages Tg2576 mice evaluated resulting neuropathology behavioral performance. We observed that performance 6-month-old significantly improved upon SO treatment, whereas no change was 11-month-old mice. Histochemical assessment amyloid plaques demonstrated SO-treated had less plaque burden than placebo-treated ones, ELISA insoluble protein fractions from brains indicated lower Aβ-42/Aβ-40 ratio group vs. controls. Altogether, our results suggest SWA-dependent amyloidosis leads to alleviated impairment only if administered course, potentially highlighting key importance sleep-based interventions clinical cohorts.

Язык: Английский

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