Translational research, Journal Year: 2022, Volume and Issue: 252, P. 21 - 33
Published: Aug. 9, 2022
Language: Английский
Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)
Published: Nov. 25, 2020
Abstract The complement cascade is a critical effector mechanism of the innate immune system that contributes to rapid clearance pathogens and dead or dying cells, as well contributing extent limit inflammatory response. In addition, some early components this have been clearly shown play beneficial role in synapse elimination during development nervous system, although excessive complement-mediated synaptic pruning adult injured brain may be detrimental multiple neurogenerative disorders. While many these later studies mouse models, observations consistent with notion reported human postmortem examination tissue. Increasing awareness distinct roles C1q, initial recognition component classical pathway, are independent rest cascade, relationship other signaling pathways inflammation (in periphery central system), highlights need for thorough understanding molecular entities facilitate successful therapeutic design, including target identification, disease stage treatment, delivery specific neurologic Here, we review evidence both effects activation products neurodegenerative Evidence requisite co-factors diverse consequences reviewed, recent support possibility pharmacological approaches suppress chronic inflammation, while preserving components, slow progression disease.
Language: Английский
Citations
208
Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 12
Published: Jan. 6, 2022
Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder with an alarming increasing prevalence. Except for the recently FDA-approved Aducanumab of which therapeutic effect not yet conclusively proven, only symptomatic medication that effective some AD patients available. In order to be able design more rational and treatments, our understanding mechanisms behind pathogenesis progression urgently needs improved. Over last years, it became increasingly clear peripheral inflammation one detrimental factors can contribute disease. Here, we discuss current how systemic intestinal (referred as gut-brain axis) inflammatory processes may affect brain pathology, specific focus on AD. Moreover, give comprehensive overview different preclinical well clinical studies link Inflammation initiation progression. Altogether, this review broadens pathology help in further research aiming identify novel targets.
Language: Английский
Citations
196
Frontiers in Neurology, Journal Year: 2020, Volume and Issue: 11
Published: Sept. 18, 2020
Alzheimer’s disease (AD) is the most prevalent form of late-onset dementia. AD affects health millions people in United States and worldwide. Currently, there are no approved therapies that can halt or reverse clinical progression AD. Traditionally, characterized first by appearance amyloid-β (Aβ) plaques followed formation intraneuronal neurofibrillary tangles (NFTs) composed hyperphosphorylated tau (p-tau). These lesions linked to synapse loss eventual cognitive impairment. Additionally, microgliosis consistently found regions brain with pathology. The role microglia onset remains unclear. Several recent reports indicate assembly multi-protein complex known as NOD, LRR, pyrin-domain containing 3 (Nlrp3) inflammasome results apoptosis spec-like protein a CARD (Asc) spec formation, which then nucleates new Aβ plaques, thus amplifying Aβ-associated NFTs also activate Nlrp3 leading enhanced tau-associated Here we will review activation innate immune response
Language: Английский
Citations
174
Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13
Published: April 26, 2022
Alzheimer's disease (AD) is the most prevalent neurodegenerative worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment AD has been only partially successful as majority pharmacotherapies on market may alleviate some symptoms. In occurrence AD, increasing attention paid neurodegeneration, while resident glial cells, like microglia are also observed. Microglia, a kind crucial cells associated with innate immune response, functions double-edge sword role in CNS. They exert beneficial detrimental influence adjacent neurons through secretion both pro-inflammatory cytokines well neurotrophic factors. addition, their endocytosis debris toxic protein Aβ tau ensures homeostasis neuronal microenvironment. this review, we will systematically summarize recent research regarding roles pathology latest microglia-associated therapeutic targets mainly including genes, anti-inflammatory genes phagocytosis at length, which contradictory controversial warrant further be investigated.
Language: Английский
Citations
174
Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 214, P. 102270 - 102270
Published: April 18, 2022
Aggregation of specific proteins are histopathological hallmarks several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions ratiometric 3 repeat (3 R) 4 (4 isoforms progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) dystrophic neurites (LNs) Parkinson's (PD) dementia with (DLB). However, mixed brain protein pathologies have been frequently observed many these diseases normal aging brains, among which Aβ/tau tau/α-Syn crosstalks received increased attention. Interestingly, studies also shown synergistic interplay Aβ, tau, α-Syn suggesting a triumvirate. In this review, we summarize the emerging evidence aggregation pathophysiology, their overlap spectrum including AD, PSP, PiD, CBD, PD DLB. We discuss prognostic advancements made biomarker imaging techniques triumvirate proteinopathies. Finally, combined therapeutic modality involving biomarkers for future combinatorial immunotherapeutic targeting more than one aggregates. hope that multitarget approach will or additive effects to manage two might uncover promising strategy personalized combination therapies. Managing by optimizing diagnostic criteria correct immunotherapies be key factor success treatment.
Language: Английский
Citations
162
Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 64, P. 101192 - 101192
Published: Oct. 13, 2020
Language: Английский
Citations
148
Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13
Published: Feb. 16, 2022
Alzheimer's disease (AD) is a common age-related neurodegenerative characterized by progressive cognitive dysfunction and behavioral impairment. The typical pathological characteristics of AD are extracellular senile plaques composed amyloid ß (Aβ) protein, intracellular neurofibrillary tangles formed the hyperphosphorylation microtubule-associated protein tau, neuron loss. In past hundred years, although human beings have invested lot manpower, material financial resources, there no widely recognized drug for effective prevention clinical cure in world so far. Therefore, evaluating exploring new targets treatment an important topic. At present, researchers not stopped pathogenesis AD, views on pathogenic factors constantly changing. Multiple evidence confirmed that chronic neuroinflammation plays crucial role AD. field neuroinflammation, nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome key molecular link neuroinflammatory pathway. Under stimulation Aβ oligomers tau aggregates, it can lead to assembly activation NLRP3 microglia astrocytes brain, thereby causing caspase-1 secretion IL-1β IL-18, which ultimately triggers pathophysiological changes decline this review, we summarize current literatures activation-related regulation mechanisms, discuss its possible roles Moreover, focusing combining with upstream downstream signaling pathway-related molecules as targets, review pharmacologically related various methods alleviate regulating inflammasome, provides ideas
Language: Английский
Citations
127
Cells, Journal Year: 2023, Volume and Issue: 12(23), P. 2726 - 2726
Published: Nov. 29, 2023
Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays pivotal role in various physiological processes. Its release is finely orchestrated suprachiasmatic nucleus, governing circadian rhythm and activating intricate hypothalamic–pituitary–adrenal (HPA) axis, vital neuroendocrine system responsible for stress response maintaining homeostasis. Disruptions cortisol regulation due to chronic stress, disease, aging have profound implications multiple bodily systems. Animal models been instrumental elucidating these complex dynamics during shedding light on interplay between physiological, neuroendocrine, immune factors response. These also revealed impact of stressors, including social hierarchies, highlighting regulation. Moreover, closely linked progression neurodegenerative diseases, like Alzheimer’s Parkinson’s, driven excessive production HPA axis dysregulation, along with neuroinflammation central nervous system. The relationship dysregulation major depressive disorder complex, characterized hyperactivity inflammation. Lastly, pain associated abnormal patterns that heighten sensitivity susceptibility. Understanding multifaceted mechanisms their effects essential, as they offer insights into potential interventions mitigate detrimental consequences conditions.
Language: Английский
Citations
126
Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(3), P. 968 - 1000
Published: June 11, 2021
Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release proinflammatory cytokines interleukin (IL)-1β and IL-18 induces pyroptosis (lytic cell death). These events drive chronic inflammation, as such, NLRP3 has been implicated in a large number human diseases. range from autoimmune conditions, simplest which is gain-of-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, disease burden indications, such atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, arthritis. The potential clinical utility inhibitors substantiated by expanding list indications activation shown play detrimental role. Studies pharmacological inhibition nonclinical models using MCC950 combination with genetics, epigenetics, analyses efficacy biologic IL-1β, anakinra canakinumab, can help prioritize trials NLRP3-directed therapeutics. Although shows excellent (nanomolar) potency high target selectivity, its pharmacokinetic toxicokinetic properties limited therapeutic development clinic. Several improved, next-generation are now trials. Hence body research plethora conditions reviewed herein may inform analysis translational value diseases significant unmet medical need.
Language: Английский
Citations
118
Cell Reports, Journal Year: 2022, Volume and Issue: 41(4), P. 111532 - 111532
Published: Oct. 1, 2022
The function and regulation of different heterogeneous reactive states astrocytes in depression remain unclear. Here, we demonstrate that neurotoxic (A1-like) are strongly induced, prior to behavioral impairments dendritic atrophy, depression-like mice. More interestingly, global or microglia-specific knockout Nod-like receptor protein 3 (Nlrp3) markedly mitigates A1-like astrocyte induction, whereas astrocyte-specific Nlrp3 depletion is ineffective. Microglial ablation also alleviates the neuronal dysfunction induced by both vitro vivo. We further show microglia NF-κB pathway activates NLRP3 inflammasome which turn caspase-1 induce secretion A1 inductors, leading production astrocytes. Altogether, this study reveals microglial induction via activating neuroinflammatory response chronic stress suggests a potential therapeutic strategy for depression.
Language: Английский
Citations
113