A cutting-edge approach based on UHPLC-MS to simultaneously investigate oxysterols and cholesterol precursors in biological samples: Validation in Huntington's disease mouse model DOI Creative Commons
Alice Passoni, Monica Favagrossa, Marta Valenza

et al.

Talanta Open, Journal Year: 2023, Volume and Issue: 9, P. 100278 - 100278

Published: Dec. 6, 2023

Brain is most cholesterol-rich organ in the body. Since cholesterol does not cross blood brain barrier, its metabolism provided situ by astrocytes and neurons, it crucial for maintaining sterol levels neuronal integrity function. Recent studies have shown that of precursors metabolites are lower brains animal models Huntington's disease (HD) while reduced catabolite detected plasma patients. In this study, we introduce a novel analytical method designed to fulfil complex requirements associated with detection neurodegenerative disorders. The allows simultaneous quantification specific set oxysterols along biological samples. proposed uses an Ultra-High-Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS) system operating multiple reaction monitoring (MRM). sterols can be found matrices either free form or esterified various fatty acids, three-step extraction procedure was devised, consisting alkaline hydrolysis, liquid-liquid final concentration omitting need solid-phase (SPE) step. validated achieved limit 10 ng/mL 1 ng/mg tissue, reaching comparable sensitivity previously published LC-MS GC-MS methods. All target analytes were separated on reverse-phase column employing segmented gradient temperature ramp. This strategy enabled elution separation all selected within 30-minutes timeframe. innovative approach employed quantify both samples from wild-type (WT) R6/2 mice, mouse model HD. results obtained sample analysis highlighted significant reduction desmosterol at 12 weeks. conclusion, paves way further development high-sensitive reproducible protocols comprehensively investigate alterations biosynthesis catabolism HD

Language: Английский

Lipid metabolism, remodelling and intercellular transfer in the CNS DOI
Sam Vanherle, Melanie Loix, Véronique E. Miron

et al.

Nature reviews. Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Language: Английский

Citations

2
Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets DOI Creative Commons

N Wang,

Peng Sun,

Qi-Qi Shen

et al.

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

Published: Jan. 7, 2025

Language: Английский

Citations

1
Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice DOI Creative Commons
Alexandra F. Putka, Varshasnata Mohanty, Stephanie M. Cologna

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106827 - 106827

Published: Feb. 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

Language: Английский

Citations

1
Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis DOI Creative Commons
Lauren Griffiths, Kristen Hawkins, Eylan Yutuc

et al.

Brain Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

Citations

1
Metabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders DOI Creative Commons

Iva Cantando,

Cristiana Centofanti,

Giuseppina D’Alessandro

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Feb. 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.

Language: Английский

Citations

8
Metabolic Reprogramming of Astrocytes in Pathological Conditions: Implications for Neurodegenerative Diseases DOI Open Access
Corrado Calì,

Iva Cantando,

María Fernanda Veloz Castillo

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8922 - 8922

Published: Aug. 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.

Language: Английский

Citations

5
Dysregulated astrocyte cholesterol synthesis in Huntington's disease: A potential intersection with other cellular dysfunctions DOI
Marta Valenza

Journal of Huntington s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: May 21, 2025

Astrocytes are key elements for synapse development and function. Several astrocytic dysfunctions contribute to the pathophysiology of various neurodegenerative disorders, including Huntington's disease (HD), an autosomal-dominant disorder that is characterized by motor cognitive defects with behavioral/psychiatric disturbances. One dysfunction in HD related astrocytes reduced cholesterol synthesis, leading a decreased availability local synaptic activity. This review describes specific role brain synthesis presents evidence supporting defective astrocyte-neuron crosstalk HD, focusing on SREBP-2, transcription factor regulates majority genes involved biosynthetic pathway. The emerging coordination SREBP-2 other physiological processes, such as energy metabolism, autophagy, Sonic Hedgehog signaling, also discussed. Finally, this intends stimulate future research directions explore whether impairment SREBP-2-mediated associates cellular disease.

Language: Английский

Citations

0
U-shaped relationship between non-high-density lipoprotein cholesterol and cognitive impairment in Chinese middle-aged and elderly: a cross-sectional study DOI Creative Commons
Lei Li,

Lingdan Zhuang,

Zichen Xu

et al.

BMC Public Health, Journal Year: 2024, Volume and Issue: 24(1)

Published: June 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.

Language: Английский

Citations

3
Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington’s Disease: Data from the TRACK and ENROLL HD Cohorts DOI
Sarah M. Gray, Jing Dai,

Anne C. Smith

et al.

Journal of Huntington s Disease, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 18

Published: Sept. 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

Language: Английский

Citations

3
When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington’s disease DOI Creative Commons
Elena Cattaneo,

Davide Scalzo,

Martina Zobel

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 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.

Language: Английский

Citations

3