NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL

NeuroMolecular Medicine, Journal Year: 2025, Volume and Issue: 27(1)

Published: Feb. 27, 2025

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic form of stroke. It caused by a cysteine-altering variant in one 34 epidermal growth factor-like repeat (EGFr) domains Notch3. NOTCH3 pathogenic variants EGFr 1–6 are associated high disease severity, whereas those 7–34 late stroke onset increased survival. However, whether how position directly affects severity remains unclear. In this study, we aimed to generate human-induced pluripotent stem cells (hiPSCs) from patients CADASIL evaluate cell phenotype protein profile generated hiPSCs lines. Six lines were generated: two variants, controls. Notch3 aggregation profiles tested established six Cell analysis revealed that did not limit reprogramming efficiency. was accumulation proteomic changes related cytoplasmic reorganization mechanisms. conclusion, our derived support clinical association between CADASIL.

Language: Английский

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Is migraine a common manifestation of CADASIL? Arguments Pros

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: April 1, 2025

Abstract Background Migraine with aura (MA) is a hallmark feature of CADASIL, hereditary small-vessel disease caused by NOTCH3 mutations. While MA prevalent in its underlying mechanisms remain unclear, and the links observed can be questioned or debated. This study examined prevalence, clinical characteristics, pathophysiology patients CADASIL. Methods Clinical experimental data were reviewed to assess sex differences, pathophysiological insights from CADASIL models confirm indisputable between migraine this unique genetic model cerebral small vessel disease. Results was 10–20 times more than general population, frequent atypical prolonged auras. The altered distribution delayed onset suggest disease-specific mechanisms. Experimental also revealed heightened susceptibility cortical spreading depression (CSD) preclinical models, linked greater fragility maintaining ionic homeostasis. Conclusion high prevalence distinct features, as well obtained at level, strongly support causal relationship mediated neurovascular dysfunction Accumulating condition sheds new light on much-debated cerebrovascular diseases.

Language: Английский

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Potential biomarkers for cerebral small vessel disease with cognitive impairment: a systematic review and meta-analysis

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 7, 2025

Cerebral small vessel disease (CSVD) is a common factor in age-related diseases such as stroke and dementia, about half of dementia patients worldwide are caused by CSVD. CSVD-related cognitive impairment (CSVD-CI) affects more elderly people, resulting economic losses burdens on families society. In recent years, circulating biomarkers have made breakthroughs played an increasingly important role the diagnosis, progression, prognosis CSVD-associated impairment, expected to be applied early clinical detection, treatment with cerebral disease. Through systematic review meta-analysis, this study aimed assess relationship between factors associated disease, especially possibility becoming potential for diagnosis. Articles published before November 2023 were searched four databases, PubMed, Web Science, Embase, Cochrane Library, identify all relevant studies reporting markers Twenty-nine articles out 2,911 finalized study. We meta-analyzed 2 or that jointly considered CSVD-CI summarized total 4 possible biomarkers: homocysteine (Hcy), high-sensitivity C-reactive protein (hs-CRP), lipoprotein-associated phospholipase A2 (Lp-PLA2), neurofilament light chain (NfL). The results revealed group had significantly higher levels Hcy hs-CRP than those CSVD-without group, whereas there was no statistically significant difference Lp-PLA2 NfL two groups. Therefore, Hcy, may

Language: Английский

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Edaravone dexborneol alleviates pericyte-mediated fibrosis depositing extracellular matrix through TGF-β1/IL-11 in cerebral small vessel disease

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 5, 2025

Chronic cerebral hypoperfusion (CCH) is a critical pathophysiological mechanism underlying small vessel disease (CSVD). Accumulating evidence have demonstrated that resident pericytes and deposit extracellular matrix (ECM) play key role in mediating fibrosis hypoxic changes. Edaravone dexborneol (EDB) known to target multiple pathways involved fibrosis. We constructed the CCH mouse models were subjected either PBS or EDB at different concentrations. Measures of cognitive function, neuronal damage, white matter lesion (WML), fibrous profiles ECM protein investigated assess effect EDB. RNA sequencing OGD was performed identify signaling pathway. observed both medium high concentrations could ameliorate CCH-induced impairment emotional disorders. Neuronal damage cortical layer hippocampus WML corpus callosum improved by EDB, which consistent with tends proteins these regions. suggested TGF-β1/IL-11 plays an important Subsequently, results confirmed cellular model. Our findings reveal pericyte-mediated depositing pathogenesis CSVD. improve symptoms mice decrease expression proteins, may be regulated TGF-β1/ IL-11. treatment, targeting fibrosis, novel therapeutic strategy for

Language: Английский

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Houshiheisan modulates the NF-κB/MLCK signaling pathway to protect the endothelial barrier in cerebral small vessel disease

Journal of Ethnopharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 119502 - 119502

Published: Feb. 1, 2025

Language: Английский

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Wearable sensors and machine learning fusion-based fall risk prediction in covert cerebral small vessel disease

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: Feb. 19, 2025

Fall risk prediction is crucial for preventing falls in patients with cerebral small vessel disease (CSVD), especially those gait disturbances. However, research this area limited, particularly the early, asymptomatic phase. Wearable sensors offer an objective method assessment. This study integrating wearable and machine learning, aimed to predict fall covert CSVD. We employed soft robotic exoskeleton (SRE) acquire characteristics surface electromyography (sEMG) system collect sEMG features, constructing three datasets: gait-only, sEMG-only, their combination. Using Support Vector Machine (SVM), Random Forest (RF), Gradient Boosting Decision Tree (GBDT), Neural Network (NN) algorithms, we developed twelve predictive models. Furthermore, integrated selected baseline data imaging markers original datasets create new datasets, constructed another optimized models using same methods. A total of 117 participants were enrolled study. Of 28 ANOVA identified 10 significant indicators. The Gait & integration dataset, analyzed SVM algorithm, demonstrated superior performance compared other model exhibited under curve (AUC) 0.986, along a sensitivity 0.909 specificity of0.923, reflecting its robust discriminatory capability. highlights essential role characteristics, electromyographic data, predicting risk. It also successfully SVM-based these features. offers valuable tool early detection CSVD patients, potentially enhancing clinical decision-making prognosis.

Language: Английский

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Carotid artery hemodynamics and geometry as predictors of cerebral small vessel disease: insights from 4D flow imaging

Neuroradiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

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Neurovascular coupling alterations related to cognitive impairment in cerebral small vessel disease: A multiscale brain network perspective

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown, P. 111311 - 111311

Published: March 1, 2025

Language: Английский

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Inhibition of astrocyte signaling leads to sex-specific changes in microglia phenotypes in a diet-based model of small cerebral vessel disease

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Hyperhomocysteinemia (HHcy)-inducing diets recapitulate small cerebral vessel disease phenotypes in mice including cerebrovascular pathology/dysfunction, neuroinflammation, synaptic deficits, and cognitive decline. We recently showed that astrocyte signaling through calcineurin(CN)/nuclear factor of activated T cells (NFATs) plays a causative role these phenotypes. Here, we assessed the impact astrocytic on microglia, which set inflammatory tone brain. Seven-to-eight-week-old male female C57BL/6J received intrahippocampal injections AAV2/5-Gfa2-EGFP (control) or adeno-associated virus (AAV) expressing NFAT inhibitor VIVIT ( i.e. , AAV2/5-Gfa2-VIVIT-EGFP). Mice were then fed with control chow (CT) B-vitamin-deficient for 12 weeks to induce HHcy. Immunohistochemistry was used assess expression pan-microglial marker Iba1 homeostatic microglial P2ry12. little sensitivity diet, AAV treatment, sex. Conversely, P2ry12 reduced HHcy diet males, but not females. Treatment males AAV-Gfa2-VIVIT prevented loss next conducted single-cell RNA sequencing (scRNAseq) determine if genes and/or clustering patterns sensitive sex-dependent manner. In disease-associated subclusters overrepresented HHcy-treated mice, while promoted appearance clusters. contrast, females less treatments, though disease-like gene also observed condition. However, very few HHcy-sensitive affected by VIVIT. The results suggest sexually dimorphic influence context disease.

Language: Английский

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TRPV4 in cerebral small vessel disease: A key interacting partner

Vascular Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 107492 - 107492

Published: March 1, 2025

Cerebral small vessel disease (cSVD) is a major cause of vascular cognitive impairment and dementia. The underlying mechanisms are centered around the dysfunction neurovascular unit include an blood-brain barrier (BBB) permeability, decreased cerebrovascular reactivity cerebral hypoperfusion. cells composing express wide variety mechanosensitive ion channels that relevant for these processes. Recent research has increasingly focused on mechanobiology microvessels with recent evidence pointing towards significant role transient receptor potential vanilloid 4 (TRPV4). This Ca2+-permeable channel regulates key physiological functions, including tone, angiogenesis, BBB integrity neuroinflammation. Beyond its role, implicates TRPV4 in pathological processes such as remodelling, impaired reactivity, dysfunction. In this review, we explore multiple roles within unit, interactions molecular partners, discuss contribution to cSVD.

Language: Английский

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