Dysbiosis of the gut microbiota and its effect on α-synuclein and prion protein misfolding: consequences for neurodegeneration DOI Creative Commons

Nasir Uddin Mahbub,

Md Minarul Islam, Seong‐Tshool Hong

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 16, 2024

Abnormal behavior of α-synuclein and prion proteins is the hallmark Parkinson’s disease (PD) illnesses, respectively, being complex neurological disorders. A primary cause protein aggregation, brain injury, cognitive loss in illnesses misfolding normal cellular (PrP C ) into an infectious form Sc ). Aggregation causes disruptions processes (PD), leading to dopamine-producing neurons motor symptoms. Alteration composition or activity gut microbes may weaken intestinal barrier make it possible for prions go from brain. The gut-brain axis linked neuroinflammation; metabolites produced by microbiota affect aggregation α-synuclein, regulate inflammation immunological responses, influence course neurotoxicity proteins, even if their targets are distinct proteins. This thorough analysis explores interactions that exist between neurodegenerative particularly involvement microbiota, a collection bacteria, archaea, fungi, viruses etc., various becoming increasingly recognized. microbiome influences neuroinflammation, neurotransmitter synthesis, mitochondrial function, integrity through axis, which contributes development progression disease. review delves molecular mechanisms underlie these relationships, emphasizing effects microbial such as bacterial lipopolysaccharides (LPS), short-chain fatty acids (SCFAs) regulating functioning. Additionally, looks at how environmental dietary decisions whether they could be risk factors illnesses. study concludes highlighting critical role plays It also provides promising direction future research treatment approaches. People afflicted difficult ailments find hope new preventive therapeutic approaches diseases better understood.

Language: Английский

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases DOI Creative Commons
Jian Sheng Loh, Wen Qi Mak, Li Tan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

Citations

231
Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

Citations

129
The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets DOI Creative Commons

Alhamdu Adamu,

Shuo Li,

Fankai Gao

et al.

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: April 12, 2024

Neuroinflammation refers to a highly complicated reaction of the central nervous system (CNS) certain stimuli such as trauma, infection, and neurodegenerative diseases. This is cellular immune response whereby glial cells are activated, inflammatory mediators liberated reactive oxygen nitrogen species synthesized. key process that helps protect brain from pathogens, but inappropriate, or protracted inflammation yields pathological states Parkinson’s disease, Alzheimer’s, Multiple Sclerosis, other disorders showcase various pathways neurodegeneration distributed in parts CNS. review reveals major neuroinflammatory signaling associated with neurodegeneration. Additionally, it explores promising therapeutic avenues, stem cell therapy, genetic intervention, nanoparticles, aiming regulate neuroinflammation potentially impede decelerate advancement these conditions. A comprehensive understanding intricate connection between diseases pivotal for development future treatment strategies can alleviate burden imposed by devastating disorders.

Language: Английский

Citations

89
Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression DOI Creative Commons
Lucas Fornari Laurindo, Jefferson Aparecido Dias, Adriano Cressoni Araújo

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as significant contributing factor. It involves the activation microglia and astrocytes, leading release pro-inflammatory cytokines chemokines infiltration peripheral leukocytes into central nervous system (CNS). These instances result in neuronal damage neurodegeneration through activated nucleotide-binding domain leucine-rich repeat containing (NLR) family pyrin protein 3 (NLRP3) nuclear factor kappa B (NF-kB) pathways decreased erythroid 2-related 2 (Nrf2) activity. Due limited effectiveness regarding inhibition neuroinflammatory targets using conventional drugs, there is challenging growth search for innovative therapies alleviating CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling Expression, Cold Exposure, Fibrin-Targeted strategies significantly promise mitigate processes. approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson’s Disease, Alzheimer’s Disease. While findings are promising, immunomodulatory often face limitations due Immune-Related Adverse Events. Therefore, conduction randomized clinical trials matter mandatory, will pave way promising future development new medicines with specific therapeutic targets.

Language: Английский

Citations

47
Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications DOI Open Access
Paras Mani Giri, Anurag Banerjee,

Arpita Ghosal

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3995 - 3995

Published: April 3, 2024

Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of total population world is affected by some form NDs, resulting in physical and cognitive disability. The most NDs include Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis, Huntington’s disease. Although are caused a complex interaction genetic, environmental, lifestyle variables, neuroinflammation known to be associated with all often leading permanent damage neurons central nervous system. Furthermore, numerous emerging pieces evidence demonstrated that inflammation not only supports progression but can also serve as an initiator. Hence, various medicines capable preventing or reducing been investigated ND treatments. While anti-inflammatory medicine has shown promising benefits several preclinical models, clinical outcomes questionable. In this review, we discuss their current treatment strategies, role pathophysiology use agents potential therapeutic option.

Language: Английский

Citations

30
Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders DOI Creative Commons
Jessica R. Cohen,

Annette Mathew,

Kirk D. Dourvetakis

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 511 - 511

Published: March 14, 2024

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s (PD), traumatic brain injury (TBI) Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions these pathogeneses is currently not clearly understood. These show dysregulated inflammatory responses, activation neurons, glial cells, neurovascular unit damage associated with excessive release proinflammatory cytokines, chemokines, neurotoxic mediators, infiltration peripheral immune cells into brain, as well entry mediators through damaged endothelial blood–brain barrier tight junction proteins. Activation leads to many molecules that cause neuroinflammation neurodegeneration. Gulf War Illness (GWI) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) also dysfunctions. Currently, there no effective disease-modifying therapeutic options available for diseases. Human induced pluripotent stem cell (iPSC)-derived astrocytes, microglia, pericytes used models drug discovery. This review highlights certain recent trends in neuroinflammatory responses iPSC-derived applications

Language: Английский

Citations

29
The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders DOI Creative Commons
Ying‐Chieh Wu,

Tizibt Ashine Bogale,

Jari Koıstınaho

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: Feb. 12, 2024

Abstract Central nervous system (CNS) accumulation of fibrillary deposits made Amyloid β (A ), hyperphosphorylated Tau or α -synuclein ( -syn), present either alone in the form mixed pathology, characterizes most common neurodegenerative diseases (NDDs) as well aging brain. Compelling evidence supports that acute neurological disorders, such traumatic brain injury (TBI) and stroke, are also accompanied by increased deposition toxic A , -syn species. While contribution these pathological proteins to neurodegeneration has been experimentally ascertained, cellular molecular mechanisms driving -syn-related damage remain be fully clarified. In last few years, studies have shown may contribute inducing and/or promoting blood–brain barrier (BBB) disruption. These can affect BBB integrity directly affecting key components pericytes endothelial cells (ECs) indirectly, macrophages activation dysfunction. Here, we summarize critically discuss findings showing how NDDs, TBI stroke. We highlight need for a deeper characterization role dysfunction macrophages, ECs improve diagnosis treatment chronic disorders.

Language: Английский

Citations

28
Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease DOI

Sujun Jiang,

Guoen Cai, Zhimin Yang

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(18), P. 11753 - 11768

Published: April 22, 2024

The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event increases the speed of Alzheimer's disease (AD). Additionally, pathogenesis AD intricate single drug may not be enough to achieve satisfactory therapeutic outcome. Herein, we reported facile effective gene therapy strategy for modulation function intervention Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) TREM2 plasmid (pTREM2) efficiently penetrate blood-brain barrier enhance accumulation at lesions with help exosomes homing ability angiopep-2 peptides. Specifically, an upregulation expression can reprogram from pro-inflammatory M1 phenotype anti-inflammatory M2 while also restoring its capacity phagocytose nerve repair function. In addition, reduces production plaques source knocking out BACE1 gene, which expected further effect AD. in vivo study suggests that TSEL through synergistic two drugs ameliorate APP/PS1 mice cognitive impairment regulating activated microglial phenotype, reducing Aβ, preventing retriggering neuroinflammation. This employs delivery dual nucleic acids, achieving AD, thus offering more options treatment

Language: Английский

Citations

25
Innate immune activation in neurodegenerative diseases DOI
Sergio Castro‐Gomez, Michael T. Heneka

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 790 - 814

Published: April 1, 2024

Language: Английский

Citations

21
Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection DOI Creative Commons
И. Ф. Беленичев, Olena Popazova,

Nina Bukhtiyarova

et al.

Antioxidants, Journal Year: 2024, Volume and Issue: 13(5), P. 504 - 504

Published: April 23, 2024

Despite the significant progress in fields of biology, physiology, molecular medicine, and pharmacology; designation properties nitrogen monoxide regulation life-supporting functions organism; numerous works devoted to this molecule, there are still many open questions field. It is widely accepted that nitric oxide (•NO) a unique molecule that, despite its extremely simple structure, has wide range body, including cardiovascular system, central nervous system (CNS), reproduction, endocrine respiration, digestion, etc. Here, we systematize •NO, contributing conditions physiological norms, as well various pathological processes, mechanisms cytoprotection cytodestruction. Current experimental clinical studies contradictory describing role •NO pathogenesis diseases CNS. We describe cytoprotective action associated with expression antiapoptotic chaperone proteins mitochondrial function. The most prominent cytodestruction—the initiation nitrosative oxidative stresses, production reactive oxygen species, participation apoptosis mitosis. formation endothelial dysfunction also considered. Moreover, focus on ways pharmacological modulation nitroxidergic allow for decrease cytodestructive increase ones.

Language: Английский

Citations

21