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Early Alzheimer's and Parkinson's disease pathology in urban children: Friend versus Foe responses--it is time to face the evidence.

Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickn … both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPπ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage con …

SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes.

Genomic multiplication of the alpha-synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resu…

Cholesterol involvement in the pathogenesis of neurodegenerative diseases.

Cholesterol, an essential component of cell membranes, plays an important role in the maintenance of cellular homeostasis and transmembrane … s of anomalous intracellular cholesterol trafficking with emphasis on cholesterol interactions with alpha-synuclein, NPC1 and NPC2 in AD, PD and NPC.

Extrapyramidal features in patients with motor neuron disease and dementia; a clinicopathological correlative study.

Motor neuron disease (MND) may be complicated by frontotemporal dementia and/or an extrapyramidal movement disorder. Several studies have id … rous neuronal inclusions and dystrophic neurites, which were reactive for ubiquitin, but not tau or alpha-synuclein. Similar pathology was either absent or much milder in cases without extrapyramidal features. This study illustrates the utility of ubiquitin immunohistochemistry in demonstrating the range of pathology in MND and provides a neuropathological correl …

[Multiple system atrophy--update].

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder, showing various combination of progressive autonomic failure, cerebellar ataxia, and levodopa poorly responsive parkinsonism. MSA accounts for more than 40% of spinocerebellar ataxias in Japan. Pathologically, myelinopathy, neuronal loss and gliosis are the cardinal features in the brain of MSA. In addition, excessive accumulation of alpha-synuclein, mostly in oligodendroglia and partly in neuron, characterizes the cellular pathology of the disorder. However, mechanism causing the disorder is not known. Clinical diagno…

Pathological involvement of the motor neuron system and hippocampal formation in motor neuron disease-inclusion dementia.

We report two patients with motor neuron disease-inclusion dementia, with special reference to the pathology of the motor neuron system and hippocampal formation. The ages of the patients at death were 55 and 62 years, and the disease durations were 8 and 3 years, respectively. The two patients exhibited progressive frontotemporal dementia in the absence of motor neuron signs. At autopsy, both cases exhibited frontotemporal lobar atrophy with ubiquitin-positive, and tau- and alpha-synuclein-negative neuronal inclusions. As expected from the clinical signs, in both cases, the upper and lower mo…

SARS-CoV-2 spike protein causes synaptic dysfunction and p-tau and α-synuclein aggregation leading cognitive impairment: The protective role of metformin.

Patients recovering from post-coronavirus disease 2019 (COVID-19) often experience cognitive dysfunction, including difficulties with focusing, conversation, or memory issues, which can persist for weeks or even months after infection. Although the persistence of the SARS-CoV-2 spike protein has been reported in both the brain and serum, and is thought to potentially contribute to the long-term effects of SARS-CoV-2 infection on the brain, the underlying mechanisms leading to cognitive dysfunction remain unclear. This study investigates the molecular mechanisms by which the SARS-CoV-2 S1 prote

Altered Autophagy-Associated Genes Expression in T Cells of Oral Lichen Planus Correlated with Clinical Features.

Oral lichen planus (OLP) is a T cell-mediated inflammatory autoimmune disease. Autophagy has emerged as a fundamental trafficking event in mediating T cell response, which plays crucial roles in innate and adaptive immunity. The present study mainly investigated the mRNA expression of autophagy-associated genes in peripheral blood T cells of OLP patients and evaluated correlations between their expression and the clinical features of OLP. Five differentially expressed autophagy-associated genes were identified by autophagy array. Quantitative real-time RT-PCR results confirmed that IGF1 expres

SNCA Overexpression Induces Apoptosis in Non-Small Cell Lung Cancer via Caspase-Dependent Signaling Pathways.

The alpha-synuclein (SNCA) gene is a Parkinson's disease (PD)-associated gene that is found to be downregulated in non-small cell lung cancer (NSCLC). Aberrant SNCA expression exerts neurotoxicity in PD by disrupting mitochondrial function, promoting protein aggregation or oxidative stress, ultimately leading to neuronal cell death. Numerous studies have hypothesized that SNCA is a tumor suppressor gene, but the underlying mechanism remains elusive. In this study, the SNCA gene is delivered to NSCLC cells via transfection of a plasmid vector with carbonate apatite (CA) nanoparticles as the del…

Purinergic modulation in Parkinson's disease: the dual role of istradefylline in motor and cognitive outcomes.

Istradefylline, a selective adenosine 2A receptor (A2AR) antagonist, was approved in 2019 as an adjuvant treatment to reduce "OFF" periods i … ntrol, it exhibits neuroprotective potential by mitigating neuroinflammation, oxidative stress, and alpha-synuclein-induced neurotoxicity. However, preclinical evidence suggests a concerning paradox: istradefylline may exacerbate cognitive decline by promoting amyloid-beta (Aβ) accumulation through the overactivity of γ-secretase and the disruption of brain-deriv …

A novel brainstem-targeted G51D α-synuclein fibril-injected mouse model exhibits sequential emergence of sleep and motor dysfunction.

Abnormal accumulation of alpha-synuclein (α-syn) is a central pathologic hallmark of synucleinopathies such as Parkinson's disease (PD), with rapid eye movement sleep behavior disorder (RBD) widely recognized as a prodromal manifestation of these disorders. Although several mouse models recapitulate the α-syn pathology, most fail to reproduce the brainstem-originating pathology propagation proposed by Braak and do not exhibit the RBD-like phenotypes expected in the prodromal phase. Here, we focused on the G51D mutation of α-syn, a familial PD-associated variant that leads to early disease onse…

Yucca filamentosa extract therapeutic potential against neuro-inflammation and demyelination through modulation of eicosanoids.

BACKGROUND: Multiple sclerosis is a chronic inflammatory disease characterized by the demyelination of nerve cells. So, it is mandatory to find out such phytochemicals that may prove to be helpful in treating neurodegeneration. Yucca filamentosa possesses anti-inflammatory, antioxidant and healing properties for the damaged neurons. METHOD: Yucca filamentosa extract (YFE) was prepared and GCMS fingerprinting and molecular docking was performed. Animals divided as Normal, Demyelination disease model, Standard care group, and three treatment groups as YFE 250 mg/kg, 500 mg/kg and 750 mg/kg. Cup

Luteolin offers novel therapeutic regimen in rotenone-induced Parkinson disease via modulation of TNF-α/FXMRP/serotonin/tyrosine hydroxylase signaling pathway.

Exposure of pesticide and complex I inhibitor, rotenone has been shown to reproduce features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and α-synuclein-positive cytoplasmic inclusions. Sixty mice were randomly divided into six groups (n=10) and orally treated for 28 consecutive days as follows; group 1: vehicle (10 mL/kg), group 2- vehicle + rotenone (10 mg/kg p.o. in 0.5% carboxymethyl cellulose (CMC), group 3 - rotenone + 100 mg/kg Luteolin, group 4 - rotenone + 200 mg/kg Luteolin, group 5 - 100 mg/kg Luteolin and group 6 - 200 mg/kg Luteolin, respect

O-GlcNacilation: молекулярный переключатель, связывающий здоровье мозга с нейродегенерацией.

Нейродегенеративные расстройства, как правило, вызваны вредным накоплением белков и повреждением нервных клеток. Послепереходная модификация, называемая N-ацетилглюкозаминовой илляцией, действует как критический регулятор в этих расстройствах, контролируя поведение белков, сигнализацию клеток и энергетический баланс. Эта модификация динамическо сбалансирована благодаря совместным действиям связанных с O переносчиков N-ацетилглюкозамина и O-GlCNAace. В здоровых мозгах O-GlcNacilation поддерживает функцию нервных клеток и выживание, но их дисбаланс способствует прогрессированию заболеваний. В ча

Совпадение в аннотации оригинала
Neurodegenerative disorders are typically caused by harmful protein accumulation and nerve cell damage. A post-translational modification ca … anges in key proteins like tau and amyloid-beta. In Parkinson's disease, it reduces the clumping of alpha-synuclein, yet may disrupt dopamine production. In amyotrophic lateral sclerosis, it protects nerve fiber transport systems. Additionally, O-GlcNAcylation plays an indispensable part in other neurodegenerative conditions, including Huntington's disease, aging …

Сравнительный анализ нервно-воспалительных путей болезни Альцгеймера, болезни Паркинсона и множественного склероза: понимание сходства и различий.

Растет интерес к нейродегенеративным болезням, усугубляющим значительное социально-экономическое бремя, вызванное старением общества. Несмотря на то, что каждая болезнь имеет различные этиологии, нейроинфламмация, как считается, играет решающую роль в болезни Альцгеймера (AD), болезни Паркинсона (PD) и множественном склерозе (MS). Помимо патогенной функции воспаления мозга, растет число свидетельств того, что иммунная реакция необходима для нейрорегенерации. Этот обзор сравнивает и контрастирует с нейроинфламационными путями, которые характерны для различных нейродегенеративных заболеваний. В

Совпадение в аннотации оригинала
Neurodegenerative diseases, contributing to the significant socioeconomic burden due to aging society, are gaining increasing interest. Desp … eta-amyloid plaques cause microglia and astrocytes to become activated in an inflammatory response. Alpha-synuclein aggregation stimulate neuroinflammation in Parkinson's disease, especially in the substantia nigra. In Multiple Sclerosis an autoimmune attack on myelin is connected to inflammation via invading immune cells. Commonalities include the release of pro …

Endothelial leakiness elicited by amyloid protein aggregation.

Alzheimer's disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding of the AD pathophysiology implicates the aggregation of amyloid beta (Aβ) as causative to neurodegeneration, with tauopathies, apolipoprotein E and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aβ deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as we

Liquid-liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson's disease pathogenesis.

Parkinson's disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (α-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of α-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in β-sheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of α-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in α-syn agg…

Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson's disease.

In patients with Parkinson's disease (PD), constipation is common, and it appears in a prodromal stage before the hallmark motor symptoms. The present study aimed to investigate whether Velusetrag, a selective 5‑HT4 receptor agonist, may be a suitable candidate to improve intestinal motility in a mouse model of PD. Five months old PrP human A53T alpha-synuclein transgenic (Tg) mice, which display severe constipation along with decreased colonic cholinergic transmission already at 3 months, were treated daily with the drug for 4 weeks. Velusetrag treatment reduced constipation by significantly …

Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils.

Immunotherapy against alpha-synuclein (α-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related α-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic α-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] α-syn transgenic mice. Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in …

Cyclic dipeptide-based small molecules modulate zinc-mediated liquid-liquid phase separation of tau.

Liquid-liquid phase separation (LLPS) is a complex physicochemical phenomenon mediated by multivalent transient weak interactions among macromolecules like polymers, proteins, and nucleic acids. It has implications in cellular physiology and disease conditions like cancer and neurodegenerative disorders. Many proteins associated with neurodegenerative disorders like RNA binding protein FUS (FUsed in Sarcoma), alpha-synuclein (α-Syn), TAR DNA binding protein 43 (TDP-43), and tau are shown to undergo LLPS. Recently, the tau protein responsible for Alzheimer's disease (AD) and other tauopathies i…