Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Язык: Английский

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Metabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Фев. 14, 2024

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by elusive underlying mechanisms. Recent attention has focused on the involvement of astrocytes and microglia in ASD pathology. These glial cells play pivotal roles maintaining neuronal homeostasis, including regulation metabolism. Emerging evidence suggests potential association between inborn errors Therefore, gaining comprehensive understanding functions crucial for development effective therapeutic interventions. This review aims to provide summary metabolism during post-natal disrupted metabolic pathways ASD, with particular emphasis those potentially important maturation microglia.

Язык: Английский

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Lipid metabolism, remodelling and intercellular transfer in the CNS

Nature reviews. Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

Язык: Английский

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Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106827 - 106827

Опубликована: Фев. 1, 2025

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited and belongs to family of nine diseases caused by a polyglutamine expansion in disease-causing protein. In SCA3, ATXN3 causes neuron loss disease-vulnerable brain regions, resulting progressive coordination ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy microstructural alterations regions SCA3 patients mouse models. However, major constituent - lipids remains understudied SCA3. study, we conducted first unbiased investigation focusing on cerebellum postmortem Liquid chromatography-mass spectrometry uncovered widespread lipid reductions with Lipid downregulation was recapitulated early- mid-stage models including transgenic YACQ84 Knock-in Q300 mice. End-stage mice displayed reduction content, highlighting targets that could benefit from early therapeutic intervention. contrast, Atxn3-Knock-out showed mild upregulation, emphasizing toxic gain-of-function mechanism underlying We conclude significantly altered establish platform continued exploration disease through interactive data visualization websites. Pronounced myelin-enriched suggest dysregulation underlie This study establishes basis future work elucidating mechanistic, biomarker, potential

Язык: Английский

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Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis

Brain Pathology, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

Disability worsening in multiple sclerosis (MS) is linked to neurodegeneration. Cholesterol homeostasis essential for normal brain function. CYP46A1, crucial cholesterol turnover and reduced some neurodegenerative diseases, a potential neuroprotective target. We hypothesized that CYP46A1 downregulated MS brains dysbalance. Mass spectrometric analysis of sterols was performed from matched plasma cerebrospinal fluid (CSF) an all-female cohort (n = 32, mean age 33). status recorded at baseline follow-up. tissue samples 11; 7 females; ages 38-67; 10 Secondary Progressive MS, 1 Primary MS; Disease Duration: 13-49 years) control 8; 3 41-68) analysed pathological regions using mass spectrometry RNA expression in-situ hybridization. Significant dysregulation 25-hydroxycholesterol, 27-hydroxycholesterol 3β-hydroxycholestenoic acid CSF correlated with disability follow-up the patient population. In tissue, cholesterol, 24S-hydroxycholesterol 24S,25-epoxycholesterol were observed white matter lesions (p < 0.05), activity. enriched neurons, reductions grey non-lesions compared controls 0.01). metabolism dysregulated associated neuron-specific expression. Modulating druggable target, may benefit progressive MS.

Язык: Английский

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U-shaped relationship between non-high-density lipoprotein cholesterol and cognitive impairment in Chinese middle-aged and elderly: a cross-sectional study

BMC Public Health, Год журнала: 2024, Номер 24(1)

Опубликована: Июнь 18, 2024

Abstract Background The relationship between blood lipids and cognitive function has long been a subject of interest, the association serum non-high-density lipoprotein cholesterol (non-HDL-C) levels impairment remains contentious. Methods We utilized data from 2011 CHARLS national baseline survey, which after screening, included final sample 10,982 participants. Cognitive was assessed using tests episodic memory intactness. used multiple logistic regression models to estimate non-HDL-C impairment. Subsequently, utilizing analysis results fully adjusted models, we explored nonlinear as well smooth curve fitting sought potential inflection points through saturation threshold effect analysis. Results showed that each unit increase in associated with 5.5% reduction odds (OR = 0.945, 95% CI: 0.897–0.996; p < 0.05). When categorical variable, or levels, were reduced by 14.2%, 20.9%, 24% Q2, Q3, Q4 groups, respectively, compared Q1. In addition, model, smoothed effects revealed U-shaped risk impairment, an point 4.83. Before point, 12.3% decrease After tipping 18.8% (All Conclusion There exists Chinese middle-aged elderly individuals, statistical significance on both sides turning points. This suggests lower higher individuals.

Язык: Английский

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Metabolic Reprogramming of Astrocytes in Pathological Conditions: Implications for Neurodegenerative Diseases

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(16), С. 8922 - 8922

Опубликована: Авг. 16, 2024

Astrocytes play a pivotal role in maintaining brain energy homeostasis, supporting neuronal function through glycolysis and lipid metabolism. This review explores the metabolic intricacies of astrocytes both physiological pathological conditions, highlighting their adaptive plasticity diverse functions. Under normal modulate synaptic activity, recycle neurotransmitters, maintain blood–brain barrier, ensuring balanced supply protection against oxidative stress. However, response to central nervous system pathologies such as neurotrauma, stroke, infections, neurodegenerative diseases like Alzheimer’s Huntington’s disease, undergo significant morphological, molecular, changes. Reactive upregulate fatty acid oxidation meet increased demands, which can be protective acute settings but may exacerbate chronic inflammation disease progression. emphasizes need for advanced genetic, tools further understand astrocyte heterogeneity reprogramming states.

Язык: Английский

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Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington’s Disease: Data from the TRACK and ENROLL HD Cohorts

Journal of Huntington s Disease, Год журнала: 2024, Номер unknown, С. 1 - 18

Опубликована: Сен. 5, 2024

Background: There is evidence for dysregulated cholesterol homeostasis in Huntington’s disease (HD). The brain-specific metabolite 24(S)-hydroxycholesterol (24(S)-OHC) decreased manifest HD. 24(S)-OHC an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower may contribute to NMDA receptor hypofunction We hypothesized changes would be associated with cognitive impairment early Objective: To determine interactions between oxysterols (24(S)-OHC, 25-OHC, and 27-OHC) at plasma levels these oxysterols, how relate performance. Methods: An vitro competition assay was used evaluate liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) measure 24(S)-OHC, 27-OHC levels, correlation analyses investigated their relationship performance on endpoints TRACK ENROLL-HD (NCT01574053). Results: In vitro, 25-OHC attenuated PAM activity receptor. Lower 24(S)/25-OHC ratios were detected participants Moderate consistent associations ratio Stroop color naming, symbol digit modality, Trails A/B, emotion recognition. Little association observed psychiatric or motor endpoints, specificity Conclusions: Our findings support growing CNS HD, demonstrate a propose that

Язык: Английский

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When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington’s disease

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Дек. 14, 2024

Abstract Trinucleotide repeats in DNA exhibit a dual nature due to their inherent instability. While rapid expansion can diversify gene expression during evolution, exceeding certain threshold lead diseases such as Huntington’s disease (HD), neurodegenerative condition, triggered by &gt;36 C–A–G exon 1 of the Huntingtin gene. Notably, discovery somatic instability (SI) tract allows these mutations, inherited from an affected parent, further expand throughout patient’s lifetime, resulting mosaic brain with specific neurons exhibiting variable and often extreme CAG lengths, ultimately leading death. Genome-wide association studies have identified genetic variants—both cis trans, including mismatch repair modifiers—that modulate SI, shown blood cells, influence HD’s age onset. This review will explore evidence for SI HD its role pathogenesis, well therapeutic implications findings. We conclude emphasizing urgent need reliable methods quantify diagnostic prognostic purposes.

Язык: Английский

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The associations between peripheral inflammatory and lipid parameters, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events

BMC Neurology, Год журнала: 2024, Номер 24(1)

Опубликована: Март 4, 2024

Abstract Background The global prevalence of VCI has increased steadily in recent years, but diagnostic biomarkers for patients with non-disabling ischemic cerebrovascular incidents (NICE) remain indefinite. primary objective this research was to investigate the relationship between peripheral serological markers, white matter damage, and cognitive function individuals NICE. Methods We collected clinical data, demographic information, medical history from 257 Using MoCA upon admission, were categorized into either normal (NCF) or groups. Furthermore, they classified as having mild hyperintensity (mWMH) severe WMH based on Fazekas scores. then compared levels markers groups Results Among NICE, 165 male 92 female. Lymphocyte count (OR = 0.448, P < 0.001) LDL-C/HDL-C 0.725, 0.028) protective factors sWMH group had a higher age inflammation lower score, lymphocyte than mWMH group. In group, (AUC 0.765, 0.740, an acceptable value diagnosis VCI. no significant differences found NCF Conclusion count, independent NICE; can be used potential biological distinguish NICE are applicable subgroups mWMH.

Язык: Английский

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