Upregulation of α-synuclein following immune activation: Possible trigger of Parkinson's disease

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 166, P. 105654 - 105654

Published: Feb. 7, 2022

Alpha-synuclein (α-syn) has been suggested to have many functions including, vesicle transport in neurons, transcriptional regulator, modulator of immune cell maturation and response, a role as an antimicrobial peptide. This protein forms insoluble aggregates, called Lewy bodies, several neurodegenerative diseases, termed synucleinopathies, including Parkinson's disease (PD), Multiple System Atrophy, Body Dementia, aggregates are also commonly found Alzheimer's disease. Moreover, multiplications point mutations the gene cause rare autosomal dominant parkinsonism, which resemble sporadic PD. It that accumulation α-syn monomeric state followed by aggregation seeding further pathogenic key steps pathogenesis synucleinopathies. The triggers neurodegeneration unknown, but inflammation caused bacterial viral pathogens or exposure environmental toxins implicated. purpose this review is present emerging evidence may play response pathogens. We recent findings suggesting upregulation levels normal infections. propose under certain conditions (e.g., dysregulated inflammatory responses due genetic predisposition aging), will form oligomers taken up nerve endings undergo axonal central nervous system, where they can aggregate into fibrils. Under unfavorable conditions, we suggest process trigger Therefore, deeper understanding roles system could provide crucial insights origins

Language: Английский

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Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

Antioxidants, Journal Year: 2022, Volume and Issue: 11(1), P. 170 - 170

Published: Jan. 17, 2022

Oxidative stress and neuroinflammation are common bases for disease onset progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting dopamine depletion, pathogenesis differs between hereditary solitary forms often unclear. addition to pathogenicity alpha-synuclein as a pathological marker, involvement itself its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, hallmark neurons, essential homeostatic maintenance adequate concentrations synaptic cleft, but it imposes burden on mitochondrial oxidative glucose metabolism, leading reactive oxygen species production. Astrocytes provide endogenous neuroprotection brain producing releasing antioxidants response stress. Additionally, protective function astrocytes can be modified microglia. Some types microglia themselves thought exacerbate pro-inflammatory factors (M1 microglia). Although these inflammatory may further trigger conversion astrocytes, induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both express receptors, upregulated presence neuroinflammation. The anti-inflammatory receptor stimulation also attracting attention because functions greatly affected depletion therapeutic replacement disease. this review article, we will focus antioxidative their synergism dopamine.

Language: Английский

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Pathogenesis of α-Synuclein in Parkinson’s Disease: From a Neuron-Glia Crosstalk Perspective

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 14753 - 14753

Published: Nov. 25, 2022

Parkinson's disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, well non-motor anosmia, depression, cognitive impairment. Pathologically, the loss dopaminergic (DA) neurons in substantia nigra (SN) accumulation α-synuclein (α-syn)-composed Lewy bodies (LBs) neurites (LNs) are key hallmarks. Glia more than mere bystanders that simply support neurons, they actively contribute to almost every aspect neuronal development function; glial dysregulation has been implicated series diseases including PD. Importantly, amounting evidence added activation neuroinflammation new features onset progression. Thus, gaining better understanding glia, especially neuron-glia crosstalk, will not only provide insight into brain physiology events but also advance our knowledge pathologies. This review addresses current α-syn pathogenesis PD, with focus on crosstalk. Particularly, transmission between α-syn-induced activation, feedbacks DA neuron degeneration thoroughly discussed. In addition, aggregation, iron deposition, regulating ferroptosis covered. Lastly, we summarize preclinical clinical therapies, targeting treatments.

Language: Английский

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Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3

Science Advances, Journal Year: 2022, Volume and Issue: 8(50)

Published: Dec. 14, 2022

Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes health and disease can contribute to synaptic damage Alzheimer's (AD). To identify SNO proteins AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 2809 sites, representing wide range of S-nitrosylated 40 postmortem non-AD human brains from patients both sexes. Integrative protein ranking revealed the top 10 increased proteins, including complement component 3 (C3), p62 (SQSTM1), phospholipase D3. Increased levels C3 were present female over male brains. Mechanistically, show that formation SNO-C3 dependent on falling β-estradiol levels, leading phagocytosis thus synapse loss consequent cognitive decline. Collectively, demonstrate robust alterations S-nitrosoproteome pathogenesis sex-dependent manner.

Language: Английский

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Astrocytic modulation of neuronal signalling

Frontiers in Network Physiology, Journal Year: 2023, Volume and Issue: 3

Published: June 1, 2023

Neuronal signalling is a key element in neuronal communication and essential for the proper functioning of CNS. Astrocytes, most prominent glia brain play role modulating at molecular, synaptic, cellular, network levels. Over past few decades, our knowledge about astrocytes their has evolved from considering them as merely glue that provides structural support to neurons, elements. Astrocytes can regulate activity neurons by controlling concentrations ions neurotransmitters extracellular milieu, well releasing chemicals gliotransmitters modulate activity. The aim this review summarise main processes through which are function. We will systematically distinguish between direct indirect pathways affect all Lastly, we summarize pathological conditions arise once these impaired focusing on neurodegeneration.

Language: Английский

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Astrocytes: The Stars in Neurodegeneration?

Biomolecules, Journal Year: 2024, Volume and Issue: 14(3), P. 289 - 289

Published: Feb. 28, 2024

Today, neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, as the average human lifespan increases, similarly grows number patients. For many decades, cognitive motoric decline has been explained by very apparent deterioration neurons in various regions brain spinal cord. However, more recent studies show that progression is greatly influenced vast population glial cells. Astrocytes are traditionally considered star-shaped cells on which rely heavily for their optimal homeostasis survival. Increasing amounts evidence depict how astrocytes lose supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many these changes similar across diseases, this review, we highlight commonalities. We discuss astrocyte dysfunction drives neuronal demise a wide range but rather than categorizing based disease, aim to provide an overview currently known mechanisms. As such, review delivers different perspective causes neurodegeneration hope encourage further cross-disease into shared mechanisms, might ultimately disclose potentially common therapeutic entry points panel diseases.

Language: Английский

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From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 986 - 986

Published: Jan. 12, 2024

Alpha-synuclein (α-syn) has gained significant attention due to its involvement in neurodegenerative diseases, particularly Parkinson's disease. However, normal function the human brain is equally fascinating. The α-syn protein highly dynamic and can adapt various conformational stages, which differ their interaction with synaptic elements, propensity drive pathological aggregation, toxicity. This review will delve into multifaceted role of different types synapses, shedding light on contributions neurotransmission overall function. We describe physiological at central including bidirectional between neurotransmitter systems.

Language: Английский

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Glutamatergic Neurotransmission in Aging and Neurodegenerative Diseases: A Potential Target to Improve Cognitive Impairment in Aging

Archives of Medical Research, Journal Year: 2024, Volume and Issue: 55(6), P. 103039 - 103039

Published: July 8, 2024

Language: Английский

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diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 293 - 293

Published: Feb. 28, 2025

The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate Nrf2 transcriptional pathway via reaction with Keap1. However, purified readily oxidized thus highly unstable. To develop as an Alzheimer's disease (AD) therapeutic, we synthesized pro-drug derivatives, among which di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted stomach prior absorption into bloodstream, exhibited improved stability bioavailability well comparable pharmacokinetics (PK) efficacy CA. test of AD transgenic mice, 5xFAD mice (or littermate controls) received drug for 3 months, followed by behavioral immunohistochemical studies. Notably, addition amyloid plaques tau tangles, hallmark human synapse loss, major correlate cognitive decline. animals receiving displayed synaptic rescue on analysis accompanied learning memory water maze test. Treatment reduced astrocytic microglial inflammation, plaque formation, phospho-tau neuritic aggregates. In toxicity studies, was safe or safer than CA, listed FDA "generally regarded safe", indicating suitable clinical trials AD.

Language: Английский

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Synaptic protein CSF levels relate to memory scores in individuals without dementia

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: March 3, 2025

Abstract Background We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), the effect amyloid positivity on these associations. Methods included 242 CN (105(43%) abnormal amyloid), 278 MCI individuals (183(66%) amyloid) from European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) Alzheimer’s Neuroimaging Initiative (ADNI). For 181 36 (ADNI) a annotation SynGO, associations word learning recall were analysed linear models. Results Subsets showed lower worse preclinical AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal MBD only, 27 proteins) non-AD 1, 7 proteins). The majority specific to clinical groups. Conclusions Synaptic disturbance-related occurred very early AD, indicating it may be relevant develop therapies targeting synapse disease.

Language: Английский

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