Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Год журнала: 2021, Номер 72, С. 101496 - 101496

Опубликована: Окт. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Язык: Английский

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The complexity of Alzheimer’s disease: an evolving puzzle

Physiological Reviews, Год журнала: 2021, Номер 101(3), С. 1047 - 1081

Опубликована: Янв. 21, 2021

The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end century identify components pathological hallmarks and genetic subtypes formulate first pathogenic hypothesis. Thanks biomarkers new technologies, concept AD then rapidly changed from a static view an amnestic dementia presenium biological entity that could be clinically manifested as normal cognition or different types. What is clearly emerging studies heterogeneous each aspect, such amyloid composition, tau distribution, relation between tau, clinical symptoms, background, thus it probably impossible explain with single process. scientific approach suffers chronological mismatches clinical, pathological, technological data, causing difficulty conceiving diagnostic gold standards creating models for drug discovery screening. A recent mathematical computer-based offers opportunity study real life provide point final missing pieces puzzle.

Язык: Английский

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Applications of Phyto-Nanotechnology for the Treatment of Neurodegenerative Disorders

Materials, Год журнала: 2022, Номер 15(3), С. 804 - 804

Опубликована: Янв. 21, 2022

The strategies involved in the development of therapeutics for neurodegenerative disorders are very complex and challenging due to existence blood-brain barrier (BBB), a closely spaced network blood vessels endothelial cells that functions prevent entry unwanted substances brain. emergence advancement nanotechnology shows favourable prospects overcome this phenomenon. Engineered nanoparticles conjugated with drug moieties imaging agents have dimensions between 1 100 nm could potentially be used ensure enhanced efficacy, cellular uptake, specific transport, delivery molecules brain, owing their modified physico-chemical features. conjugates medicinal plants, or components known as nano phytomedicine, been gaining significance lately novel neuro-therapeutics natural abundance, promising targeted lesser potential show adverse effects. In present review, application, recent trends combined phytomedicine treatment neurological (ND) compared conventional therapies, addressed. Nanotechnology-based efforts performed bioinformatics early diagnosis well futuristic precision medicine ND also discussed context computational approach.

Язык: Английский

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Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer’s disease

Ageing Research Reviews, Год журнала: 2021, Номер 68, С. 101339 - 101339

Опубликована: Апрель 5, 2021

Язык: Английский

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Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery

Molecular Neurodegeneration, Год журнала: 2021, Номер 16(1)

Опубликована: Авг. 12, 2021

Mass spectrometry-based proteomics empowers deep profiling of proteome and protein posttranslational modifications (PTMs) in Alzheimer's disease (AD). Here we review the advances limitations historic recent AD proteomic research. Complementary to genetic mapping, studies not only validate canonical amyloid tau pathways, but also uncover novel components broad networks, such as RNA splicing, development, immunity, membrane transport, lipid metabolism, synaptic function, mitochondrial activity. Meta-analysis seven datasets reveals 2,698 differentially expressed (DE) proteins landscape brain (n = 12,017 proteins/genes), covering 35 reported genes risk loci. The DE contain cellular markers enriched neurons, microglia, astrocytes, oligodendrocytes, epithelial cells, supporting involvement diverse cell types pathology. We discuss hypothesized protective or detrimental roles selected proteins, emphasizing top "amyloidome" (all biomolecules plaques) progression. Comprehensive PTM analysis represents another layer molecular events AD. In particular, PTMs are correlated with stages indicate heterogeneity individual patients. Moreover, unprecedented coverage biofluids, cerebrospinal fluid serum, procures putative biomarkers through meta-analysis. Thus, proteomics-driven systems biology presents a new frontier link genotype, proteotype, phenotype, accelerating development improved models treatment strategies.

Язык: Английский

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New approaches to symptomatic treatments for Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2021, Номер 16(1)

Опубликована: Янв. 13, 2021

Successful development of agents that improve cognition and behavior in Alzheimer's disease (AD) is critical to improving the lives patients manifesting symptoms this progressive disorder.There have been no recent approvals cognitive enhancing for AD. There are currently 6 enhancers Phase 2 trials 4 phase 3. They represent a variety novel mechanisms. has progress developing new treatments neuropsychiatric AD with advances treatment insomnia, psychosis, apathy, agitation AD-related psychotropic 7 3 trials. Many mechanisms being explored behavioral targets. Progress trial designs, outcomes measures, population definitions conduct symptomatic AD.Advances combined enhanced methods promise address unmet needs improved amelioration symptoms.

Язык: Английский

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Alzheimer’s Disease: An Update and Insights Into Pathophysiology

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

Опубликована: Март 30, 2022

Alzheimer’s disease (AD) is an irreversible brain disorder associated with slow, progressive loss of functions mostly in older people. The processes start years before the symptoms are manifested at which point most therapies may not be as effective. In hippocampus, key proteins involved JAK2/STAT3 signaling pathway, such p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to elevated various models AD. addition neurons, glial cells astrocytes also play a crucial role progression Without having significant effect on tau amyloid pathologies, pathway reactive exhibits behavioral impact experimental Cholinergic atrophy AD has been traced trophic failure NGF metabolic essential for survival maintenance basal forebrain cholinergic neurons (BFCN). AD, there alteration conversion proNGF mature (mNGF), increase degradation biologically active mNGF. Thus, application exogenous mNGF studies was shown improve recovery atrophic BFCN. Furthermore, it now coming light that FGF7/FGFR2/PI3K/Akt mediated by microRNA-107 pathogenesis. Vascular dysfunction long cognitive decline increased risk factors higher cerebral beta-amyloid (Aβ) burden, while synergistically acting Aβ induce decline. apolipoprotein E4 polymorphism just one vascular factors, but prevalent genetic factor More recently, research focus shifted toward metabolisms neurotransmitters, major minor nutrients, thus giving rise metabolomics, important “omics” tool diagnosis prognosis neurodegenerative diseases based individual’s metabolome. This review will therefore proffer better understanding novel pathways neural mechanisms elaborate potential links between recent developments “omics”-based biomarkers

Язык: Английский

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Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function

Acta Neuropathologica, Год журнала: 2021, Номер 143(2), С. 179 - 224

Опубликована: Дек. 1, 2021

Abstract In neurological diseases, the actions of microglia, resident myeloid cells CNS parenchyma, may diverge from, or intersect with, those recruited monocytes to drive immune-mediated pathology. However, defining precise roles each cell type has historically been impeded by lack discriminating markers and experimental systems capable accurately identifying them. Our ability distinguish microglia from in neuroinflammation advanced with single-cell technologies, new drugs that identify deplete them, respectively. Nevertheless, focus individual studies on particular types, diseases approaches limited our connect phenotype function more widely across diverse pathologies. Here, we critically review, tabulate integrate disease-specific functions immune profiles provide a comprehensive atlas responses viral encephalitis, demyelination, neurodegeneration ischemic injury. emphasizing differential severe neuroinflammatory disease inflammatory pathways common equally incapacitating less inflammation. We examine these findings context human highlight benefits inherent limitations animal models impede facilitate clinical translation. This enables us contrasting, non-redundant often opposing could be targeted therapeutically.

Язык: Английский

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The State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease

Journal of Central Nervous System Disease, Год журнала: 2021, Номер 13

Опубликована: Янв. 1, 2021

Alzheimer’s disease (AD) is a chronic disabling that affects the central nervous system. The main consequences of AD include decline cognitive functions and language disorders. One causes leading to decrease neurotransmitter acetylcholine (ACh) levels in brain, part due higher activity acetylcholinesterase (AChE), enzyme responsible for its degradation. Many inhibitors (AChEIs), both natural synthetic, have been developed used through years counteract progression disease. first such drugs approved therapeutic use was tacrine, binds reversible bond enzyme. However, tacrine has since withdrawn because adverse effects. Currently, donepezil galantamine are very promising AChEIs with clinical benefits. Moreover, rivastigmine considered pseudo-irreversible compound anti-AChE action, providing similar effects at level. purpose this review provide an overview what published over last decade on effectiveness AD, analysing most relevant issues under methodological profiles consequent possible welfare whole world. Furthermore, novel approaches also discussed.

Язык: Английский

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Omics sciences for systems biology in Alzheimer’s disease: State-of-the-art of the evidence

Ageing Research Reviews, Год журнала: 2021, Номер 69, С. 101346 - 101346

Опубликована: Апрель 27, 2021

Язык: Английский

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