Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

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

Опубликована: Июнь 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Язык: Английский

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Plasma membrane integrity in health and disease: significance and therapeutic potential

Cell Discovery, Год журнала: 2021, Номер 7(1)

Опубликована: Янв. 19, 2021

Maintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust repair mechanisms have evolved to counteract the eminent threat a torn membrane. Different bio-physical parameters required efficient are now emerging from different research groups. However, less known about when these come into play. This review focuses on existence disruptions in both physiological pathological conditions, across multiple types, albeit degrees. Fundamentally, irrespective source disruption, aberrant calcium influx common stimulus that activates response. Inadequate responses can tip balance between physiology pathology, highlighting significance integrity. For example, an over-activated response promote cancer invasion, while inability efficiently drive neurodegeneration muscular dystrophies. The interdisciplinary view explored here emphasises widespread potential targeting therapeutic purposes.

Язык: Английский

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Impact of nanoplastics on Alzheimer ’s disease: Enhanced amyloid-β peptide aggregation and augmented neurotoxicity

Journal of Hazardous Materials, Год журнала: 2024, Номер 465, С. 133518 - 133518

Опубликована: Янв. 13, 2024

Язык: Английский

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Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia

Journal of Neurochemistry, Год журнала: 2019, Номер 155(6), С. 650 - 661

Опубликована: Дек. 24, 2019

Abstract Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder causing memory loss, language problems and behavioural disturbances. AD associated with accumulation of fibrillar amyloid‐β (Aβ) formation neurofibrillary tau tangles. Fibrillar Aβ itself represents a danger‐associated molecular pattern, which recognized by specific microglial receptors. One key players NOD‐, LRR‐ pyrin domain‐containing 3 (NLRP3) inflammasome, whose activation has been demonstrated in patient brains transgenic animal models AD. Here, we investigated whether oligomers or protofibrils that represent lower aggregates prior to deposition are able activate NLRP3 inflammasome subsequent interleukin‐1 beta (IL‐1β) release microglia. In our study, used preparations different sizes: small structure was confirmed atomic force microscopy. Primary cells from C57BL/6 mice were treated respective activation, represented caspase‐1 cleavage, IL‐1β production, apoptosis‐associated speck‐like protein containing CARD speck analysed. Both low weight induced significant increase release. Inflammasome detection active caspase‐1. The inhibitor MCC950 completely inhibited Aβ‐induced immune response. Our results show activated not only as reported before, but also protofibrils, highlighting possibility these species may initiate innate responses central nervous system onset deposition. image Cover Image for this issue: https://doi.org/10.1111/jnc.14773 .

Язык: Английский

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The Toxicity and Polymorphism of β-Amyloid Oligomers

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(12), С. 4477 - 4477

Опубликована: Июнь 24, 2020

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer's disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous their size, structure cytotoxicity, making corresponding studies tough to carry out. Nevertheless, number have recently made remarkable progress describing characteristics pathogenicity Aβos. We here review mechanisms which exert neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation tau pathological induction. also summarize such as morphology cytotoxicity dimers, trimers, Aβ*56 spherical oligomers, suggest may different at phases pathogenesis, resulting differential consequences on neuronal synaptotoxicity survival. warranted investigate temporal sequence human brain examine relationship between impairment.

Язык: Английский

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Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июль 30, 2021

Abstract Amyloid-β peptide (Aβ) forms metastable oligomers >50 kDa, termed AβOs, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including mislocalization. In neurons, accumulates in endo-lysosomal vesicles low pH. Here, we show the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to pH, expense fibril formation. The pH-induced promotion formation high concentration together enable extensive Aβ42 under physiological conditions. Exploiting enhanced dimeric variant dimAβ furthermore demonstrate targeting AβOs dendritic spines, potent induction missorting, a key factor tauopathies, impaired neuronal activity. results suggest endosomal/lysosomal system major site for pathomechanistically relevant AβOs.

Язык: Английский

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Imaging Amyloid‐β Membrane Interactions: Ion‐Channel Pores and Lipid‐Bilayer Permeability in Alzheimer's Disease

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(25)

Опубликована: Март 6, 2023

The accumulation of the amyloid-β peptides (Aβ) is central to development Alzheimer's disease. mechanism by which Aβ triggers a cascade events that leads dementia topic intense investigation. self-associates into series complex assemblies with different structural and biophysical properties. It interaction these oligomeric, protofibril fibrillar lipid membranes, or membrane receptors, results in permeability loss cellular homeostasis, key event disease pathology. can have an array impacts on reports included: carpeting effect; detergent ion-channel pore formation. Recent advances imaging interactions are providing clearer picture induced disruption. Understanding relationship between structures will inform therapeutics targeting cytotoxicity.

Язык: Английский

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The link between metabolic syndrome and Alzheimer disease: A mutual relationship and long rigorous investigation

Ageing Research Reviews, Год журнала: 2023, Номер 91, С. 102084 - 102084

Опубликована: Окт. 5, 2023

Язык: Английский

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Lecanemab‐Associated Amyloid‐β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease

Annals of Neurology, Год журнала: 2025, Номер 97(5), С. 993 - 1006

Опубликована: Янв. 6, 2025

Objective The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted less decline on measures of cognition function than placebo. Herein, we aimed to characterize amyloid‐β (Aβ) protofibril (PF) captured by human cerebrospinal fluid (CSF) from living participants with different stages AD, which enable an enhanced understanding the dynamic changes lecanemab‐associated Aβ‐PF (Lec‐PF) vivo. Methods We newly developed a unique highly sensitive immunoassay method using selectively captures Lec‐PF. CSF level Lec‐PF, Aβ42, Aβ40, p‐tau181, p‐tau 217, total tau, neurogranin were measured Japanese (n = 163). this study consisted 48 cognitively unimpaired Aβ‐negative (CU–), 8 impaired diagnosed as suspected non‐Alzheimer's pathophysiology, 9 Aβ‐positive (CU+), 34 mild cognitive impairment (MCI+), 64 dementia (AD+). Results Lec‐PF levels significantly increased groups MCI+ AD+ compared CU– group. Notably, modest correlation plaque‐associated biomarkers stronger neurodegeneration biomarkers, such tau neurogranin, suggesting proximally reflect well amount senile plaques. Interpretation This is first report describing species supporting correlated may explain mechanism clinical effect lecanemab. ANN NEUROL 2025;97:993–1006

Язык: Английский

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Pharmacotherapy of Alzheimer’s Disease: Seeking Clarity in a Time of Uncertainty

Frontiers in Pharmacology, Год журнала: 2020, Номер 11

Опубликована: Март 24, 2020

Alzheimer's disease (AD) is recognized as a major health hazard that mostly affects people older than 60 years. AD one of the biggest medical, economic and social concerns to patients their caregivers. ranked 5th leading cause global deaths in 2016 by World Health Organization (WHO). Many drugs targeting production, aggregation clearance Aβ plaques failed give any conclusive clinical outcomes. This mainly stems from fact not attributed single-gene mutation. Two hallmarks AD, neurofibrillary tangles (NFTs) can simultaneously induce other etiologies where every pathway loop consequential events. Therefore, focus recent research has shifted exploring such neuroinflammation central hyperexcitability. Neuroinflammation results hyperactivation microglia astrocytes release pro-inflammatory cytokines due neurological insults caused NFTs, eventually synaptic dysfunction neuronal death. review will report failures side effects many anti-Aβ drugs. In addition, emerging treatments nonsteroidal anti-inflammatory (NSAIDs) receptor-interacting serine/threonine protein kinase 1 (RIPK1) restore calcium (Ca2+) dyshomeostasis physiological function clearing plaques, respectively, be deliberately discussed. Besides, novel pharmacotherapy strategies treating including disease-modifying agents (DMTs), repurposing medications used treat non-AD illnesses multi target-directed ligands (MTDLs) also are reviewed. These approaches open new doors development therapy, especially combination therapy cater for several targets simultaneously, hence, effectively slowing or stopping AD.

Язык: Английский

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