Synergistic effects of mutation and glycosylation on disease progression

Frontiers in Molecular Biosciences, Journal Year: 2025, Volume and Issue: 12

Published: Feb. 4, 2025

Glycosylation, a post-translational modification, plays crucial role in proper localization and function of proteins. It is regulated by multiple glycosyltransferases can be influenced various factors. Inherited missense mutations glycosylated proteins such as NOTCH3, Low-density lipoprotein receptor (LDLR), Amyloid precursor protein (APP) could affect their glycosylation states, leading to cerebral small vessel disease, hypercholesterolemia, Alzheimer’s respectively. Additionally, physiological states aging-related conditions the expression levels glycosyltransferases. However, interplay between changes remains poorly understood. This mini-review summarizes effects on transmembrane with pathogenic mutations, including LDLR, APP. We highlight synergistic contributions amino acids mutant alterations molecular pathogenesis.

Language: Английский

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Decreased Brain Interstitial Fluid Dynamics Is Associated with Risk of Alzheimer’s Disease-Related Cognitive Decline

Brain Research Bulletin, Journal Year: 2025, Volume and Issue: 224, P. 111295 - 111295

Published: March 11, 2025

Diffusion-tensor image analysis along the perivascular space (ALPS) index that has potential to reflect brain interstitial fluid (ISF) dynamics may predict development of Alzheimer's Disease (AD). We aimed study whether ISF indicated by ALPS relate AD dementia diagnosis and AD-related changes. This included a discovery cohort (n = 180) validation 127), which were composed cognitively normal, subjective memory concern, mild cognitive impairment, subjects. All participants underwent magnetic resonance imaging examination neuropsychological evaluation. The diffusivities diffusion-tensor calculated. support vector machine (SVM) model for was built in validated cohort. Linear mixed-effects models used evaluate association between decline. Cox regression risk dementia. There lower median group compared other groups (all P < 0.05) both cohorts. SVM produced an AUC 0.802 (P 0.001) 0.783 external 0.001). Higher levels associated with less decline Moreover, baseline had greater converting 0.014). based on effective diagnosis, higher are These findings suggest provide useful progression or treatment biomarker.

Language: Английский

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Glymphatic system dysfunction and cerebrospinal fluid retention in gliomas: evidence from perivascular space diffusion and volumetric analysis

Cancer Imaging, Journal Year: 2025, Volume and Issue: 25(1)

Published: April 7, 2025

Abstract Background Gliomas may impair glymphatic function and alter cerebrospinal fluid (CSF) dynamics through structural brain changes, potentially affecting peritumoral edema (PTBE) clearance. This study investigated the impact of gliomas on system CSF volume via diffusion tensor imaging analysis along perivascular space (DTI-ALPS) volumetric magnetic resonance (MRI), which clarified relationships between tumor characteristics disruption. Methods In this prospective study, 112 glioma patients 56 healthy controls underwent MRI to calculate DTI-ALPS indices perform analyses CSF, tumor, PTBE. Statistical were used assess index, volume, PTBE clinical characteristics. Results Glioma had significantly lower (1.266 ± 0.258 vs. 1.395 0.174, p < 0.001) greater volumes (174.53 34.89 cm³ 154.25 20.89 cm³, than did. The index was inversely correlated with ( r = -0.353, -0.266, 0.015). High-grade associated larger (all 0.001). Tumor grade emerged as an independent predictor in multivariate (β -0.244, 0.011). Conclusion are significant dysfunction, evidenced by reduced increased volumes. serves a potential biomarker disruption patients, offering insights into tumor-related changes pathophysiology brain-tumor interactions.

Language: Английский

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NOTCH3 Mutation Causes Glymphatic Impairment and Promotes Brain Senescence in CADASIL

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 1, 2025

ABSTRACT Aims The aim of this study is to investigate the role glymphatic function cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL), most common monogenic small vessel disease caused by NOTCH3 mutation, explore potential therapeutic strategies improve function. Methods We assessed influx efflux in CADASIL mouse models ( Notch3 R170C ) correlated these findings with brain atrophy patients. also investigated underlying mechanisms impairment, focusing expression AQP4 astrocytic endfeet. Results exhibited both impaired efflux, which impedes waste clearance promotes senescence. In accordance, patients associated perivascular space enlargement, indicating that impairment contributes advanced senescence CADASIL. malfunction attributed diminished endfeet, core mediator activity. Mechanistically, regulated NOTCH3‐RUNX1‐CMYB signaling. Reinforcing astrocytes AAV‐based therapy resumes functions mice, further prevents Conclusion propose reinforcing a promising strategy

Language: Английский

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Developing zebrafish models of Notch-related CNS pathologies

Neuroscience & Biobehavioral Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 106059 - 106059

Published: Feb. 1, 2025

Language: Английский

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Glymphatic system: a self-purification circulation in brain

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

Published: Feb. 12, 2025

The glymphatic system theory introduces a new perspective on fluid flow and homeostasis in the brain. Here, cerebrospinal interstitial (CSF-ISF) moves from perivascular spaces (PVS) of arteries to those veins for drainage. Aquaporin-4 (AQP4) plays crucial role driving within PVS. impairment AQP4 is closely linked dysfunction system. function less active during waking but enhanced sleep. efficiency decreases with aging. Damage will give rise development progression many brain diseases, such as Alzheimer’s disease (AD), Parkinson’s (PD), chronic traumatic encephalopathy (CTE), vascular dementia (VaD). we reviewed previous research associated system, including its concepts, principles, influencing factors. We hypothesize that could be target prevention treatment certain diseases through regulation

Language: Английский

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Various diseases and conditions are strongly associated with the next-generation epigenetic aging clock CheekAge

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

Published: March 7, 2025

Epigenetic aging clocks represent contemporary biomarkers that predict age using methylomic data. These models can be categorized as first-generation estimate chronological or next-generation are designed to associate with health, lifestyle, and/or outcomes. Recently, we created a buccal clock called CheekAge associates all-cause mortality risk in older adults. To better understand our model, collated 25 Infinium MethylationEPIC datasets the Gene Expression Omnibus database and analyzed ability of five other well-known distinct health disease signals. outcompeted every tested by significantly associating total 33 different variables, including human immunodeficiency virus, major depressive disorder, psychological trauma, prediabetes, body mass index, non-alcoholic fatty liver disease, pulmonary fibrosis, exposure chemical endocrine disruptor PBB-153, various cancers tumors. Of six tested, outperformed clocks. underlying biology CheekAge, iteratively removed CpG inputs identify DNA methylation sites promoted antagonized each association. Finally, performed detailed enrichment analyses on these unveil overrepresented biological processes transcription factor targets.

Language: Английский

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Assessing Changes on Large Cerebral Arteries in CADASIL: Preliminary Insights from a Case-Control Analysis

Journal of Stroke and Cerebrovascular Diseases, Journal Year: 2025, Volume and Issue: unknown, P. 108294 - 108294

Published: March 1, 2025

Language: Английский

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The Pathobiology of Cerebrovascular Lesions in CADASIL Small Vessel Disease

Basic & Clinical Pharmacology & Toxicology, Journal Year: 2025, Volume and Issue: 136(5)

Published: March 27, 2025

ABSTRACT Cerebral small vessel disease (cSVD) is a significant global health issue, accounting for approximately 25% of ischemic strokes and 20% all dementia cases. CADASIL, the most common monogenic form cSVD, caused by stereotyped mutations in NOTCH3 receptor that alter number cysteine residues its extracellular domain (Notch3 ECD ). The two hallmark features CADASIL are loss arterial smooth muscle cells (SMCs) abnormal accumulation Notch3 , without associated transmembrane intracellular domain. Notably, cysteine‐altering prevalent general population, although they not directly with classical disease, still linked to an elevated risk stroke dementia. predominantly expressed mural blood vessels plays essential role development, maintenance, function survival SMCs. Recent research has challenged loss‐of‐function hypothesis, instead implicating aggregation, involving both mutant wild‐type NOTCH3, as primary driver vascular pathology CADASIL. Consequently, therapeutic strategies targeting reduction levels brain arteries, such antisense therapies, considered highly promising clinical development.

Language: Английский

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The Bidirectional Role of Hypoxia-Inducible Factor 1 Alpha in Vascular Dementia Caused by Chronic Cerebral Hypoperfusion

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Language: Английский

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