A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice DOI Creative Commons

Wei-Ping Dai,

Mengqian Yang,

Pei Xia

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 16, 2022

Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage molecules in cerebrospinal fluid to peripheral immune system. Their potential role depression-like behaviour has not been investigated. Here, we show mice, sub-chronic variable stress as a model impairs meningeal females but males. Manipulations regulate sex difference susceptibility stress-induced depression- and anxiety-like behaviors well alterations medial prefrontal cortex ventral tegmental area, brain regions critical emotional regulation. Together, our findings suggest lymphatic impairment contributes that restoration might have modulation behaviour.

Language: Английский

Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation DOI Creative Commons
Mergim Ramosaj, Sofia Madsen,

Vanille Maillard

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Dec. 21, 2021

Abstract Neural stem/progenitor cells (NSPCs) generate new neurons throughout adulthood. However, the underlying regulatory processes are still not fully understood. Lipid metabolism plays an important role in regulating NSPC activity: build-up of lipids is crucial for proliferation, whereas break-down has been shown to regulate quiescence. Despite their central cellular lipid metabolism, droplets (LDs), storing organelles, NSPCs remains underexplored. Here we show that LDs highly abundant adult mouse NSPCs, and LD accumulation significantly altered upon fate changes such as quiescence differentiation. proliferation influenced by number LDs, inhibition build-up, breakdown or usage, asymmetric inheritance during mitosis. Furthermore, high LD-containing have increased metabolic activity capacity, but do suffer from oxidative damage. Together, these data indicate instructive driving behaviour.

Language: Английский

Citations

79
Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination DOI Creative Commons

Na Wang,

Minghui Wang, Suren Jeevaratnam

et al.

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Nov. 23, 2022

Abstract Background Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles the clearance lipid-rich cellular debris upon myelin damage or demyelination, common pathogenic event neuronal disorders. Apolipoprotein E (apoE) plays pivotal role brain homeostasis; however, apoE isoform-dependent mechanisms regulating microglial response demyelination remain unclear. Methods To determine how isoforms impact damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) 0.2% cuprizone (CPZ) for four weeks induce brain. examine effects on subsequent remyelination, was switched back regular chow an additional two weeks. After treatment, brains collected subjected immunohistochemical biochemical analyses assess myelination status, responses, their capacity clearance. Bulk RNA sequencing performed corpus callosum (CC) address molecular underpinning apoE-mediated activation demyelination. Results We demonstrate dramatic differences function cuprizone-induced ApoE2 hyperactive more efficient clearing debris, whereas apoE4 displayed less activated phenotype reduced efficiency, compared apoE3 microglia. Transcriptomic profiling revealed that molecules known modulate functions had differential expression patterns manner. Importantly, excessive buildup droplets, consistent impairment metabolism, apoE2 superior ability metabolize enriched lipids. Further, apoE2-TR greater extent remyelination; remyelination compromised apoE4-TR mice. Conclusions Our findings provide critical mechanistic insights into differentially regulate maintenance dynamics, which may inform novel therapeutic avenues targeting dysfunctions

Language: Английский

Citations

48
Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism DOI Creative Commons
Marlena Zyśk, Chiara Beretta, Luana Naia

et al.

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Feb. 20, 2023

Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts aggregated amyloid-beta (Aβ). However, which way these Aβ deposits influence their production remain unclear.The aim present study was investigate how pathology affects mitochondria functionality and overall metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived were exposed sonicated Aβ42 fibrils for 7 days analyzed over time using different experimental approaches.Our results show maintain stable production, initially increased mitochondrial fusion, eventually Aβ-mediated stress led abnormal swelling excessive fission. Moreover, we detected levels phosphorylated DRP-1 Aβ-exposed astrocytes, co-localized with lipid droplets. Analysis ATP levels, when blocking certain stages pathways, indicated metabolic shift peroxisomal-based fatty acid β-oxidation glycolysis.Taken together, our data conclude profoundly changes entire could result disturbed homeostasis aggravated progression.

Language: Английский

Citations

41
Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells DOI Creative Commons
Suelen da Silva Gomes Dias, Tamires Cunha‐Fernandes, Luciana Souza‐Moreira

et al.

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: March 8, 2023

Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including droplet (LD) biogenesis, has been associated with viral replication pathogenesis of different viruses. However, the mechanisms LD formation their roles ZIKV neural cells are still unclear. Here, we demonstrate that regulates expression pathways upregulation activation lipogenesis-associated transcription factors decreased lipolysis-associated proteins, leading significant accumulation human neuroblastoma SH-SY5Y stem (NSCs). Pharmacological inhibition DGAT-1 vitro an vivo mouse model infection. In accordance role LDs regulation inflammation innate immunity, show blocking major inflammatory cytokine production brain. Moreover, observed inhibited weight loss mortality induced by vivo. Our results reveal biogenesis triggered crucial step for cells. Therefore, targeting metabolism may represent potential strategies anti-ZIKV treatment development.

Language: Английский

Citations

27
Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders DOI Creative Commons

Xiaojie Zhao,

Siwei Zhang, Alan R. Sanders

et al.

Complex Psychiatry, Journal Year: 2023, Volume and Issue: 9(1-4), P. 154 - 171

Published: Jan. 1, 2023

<b><i>Background:</i></b> Lipids are essential components of the structure and for function brain cells. The intricate balance lipids, including phospholipids, glycolipids, cholesterol, cholesterol ester, triglycerides, is crucial maintaining normal function. roles lipids lipid droplets their relevance to neurodegenerative neuropsychiatric disorders (NPDs) remain largely unknown. <b><i>Summary:</i></b> Here, we reviewed basic role as well a specific organelle, droplets, in function, highlighting potential impact altered metabolism pathogenesis Alzheimer’s disease (AD) NDPs. <b><i>Key Messages:</i></b> Brain dysregulation plays pivotal progression NPDs AD schizophrenia. Understanding cell type-specific mechanisms these diseases identifying better diagnostic biomarkers developing therapeutic strategies aiming at restoring homeostasis.

Language: Английский

Citations

26
Lipid Droplets and Neurodegeneration DOI
Keya Mallick,

Shuchismita Paul,

Sayani Banerjee

et al.

Neuroscience, Journal Year: 2024, Volume and Issue: 549, P. 13 - 23

Published: May 6, 2024

Language: Английский

Citations

17
Intermittent Fasting Ameliorates β‐Amyloid Deposition and Cognitive Impairment Accompanied by Decreased Lipid Droplet Aggregation Within Microglia in an Alzheimer's Disease Model DOI Open Access
Liangwei Wu, Yang Zhao, Xiaokang Gong

et al.

Molecular Nutrition & Food Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

ABSTRACT Scope: Alzheimer's disease (AD) is the most prevalent form of dementia, lack effective therapeutic interventions. In this study, we investigate impact intermittent fasting (IF), an alternative strategy calorie restriction, on cognitive functions and AD‐like pathology in a transgenic mouse model AD. Methods results: APP/PS1 mice at 6 months were randomly allocated to two dietary groups: one receiving ad libitum (AL) feeding other undergoing IF for 1 month. Y maze, Barnes western blotting, immunofluorescence employed. Behavioral assessments revealed that APP/PS1‐IF group demonstrated notable improvements function compared AL group. Further analysis showed microglia exhibited enhanced phagocytic activity, characterized by prominent enlargement soma reduced complexity their processes. Importantly, significantly decreased accumulation lipid droplets (LDs) within microglia. These with less LDs may contribute β‐amyloid (Aβ) phagocytosis, thereby ameliorating Aβ deposition brains mice. Conclusion: Our findings demonstrate ameliorates amyloid deficits AD mice, which associated reduction microglia, providing support use intervention against pathology.

Language: Английский

Citations

1
Arsenic Exposure Induces Neural Cells Senescence and Abnormal Lipid Droplet Accumulation Leading to Social Memory Impairment in Mice DOI
Bo Zhang, Junhong Chen, Jiaojiao Wang

et al.

Environmental Pollution, Journal Year: 2025, Volume and Issue: 368, P. 125779 - 125779

Published: Jan. 31, 2025

Language: Английский

Citations

1
The circular RNA circbabo(5,6,7,8S) regulates lipid metabolism and neuronal integrity via TGF-β/ROS/JNK/SREBP signaling axis in Drosophila DOI Creative Commons
Jie Sheng, Xuemei Zhang, Weihong Liang

et al.

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 5, 2025

Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation LDs nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) new class non-coding regulatory widely expressed eukaryotes. However, only subset has been functionally characterized. Here, we identified characterized circular RNA circbabo(5,6,7,8S) regulates lipogenesis neuronal integrity Drosophila melanogaster. derived from babo locus encodes type I receptor for transforming growth factor β (TGF-β). Depletion flies causes elevated droplet accumulation, progressive photoreceptor cell loss shortened lifespan, phenotypes rescued by restoring expression. In addition, RNA-seq epistasis analyses reveal these abnormalities caused aberrant activation SREBP signaling pathway. Furthermore, circbabo(5,6,7,8S)-depleted tissues display enhanced TGF-β pathway compromised mitochondrial function, resulting upregulation reactive oxygen species (ROS). Moreover, provide evidence protein circbabo(5,6,7,8S)-p, inhibits interfering assembly babo/put heterodimer complex. Lastly, show dysregulation ROS/JNK/SREBP cascade responsible LD neurodegeneration, lifespan elicited depletion. Our study demonstrates physiological protein-coding circRNA regulating metabolism integrity.

Language: Английский

Citations

1
Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer's disease DOI Creative Commons
Ni Wang,

Yining Pan,

Skylar C Starling

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract INTRODUCTION Loss‐of‐function variants of the ABCA7 gene are associated with an increased risk Alzheimer's disease (AD). How neuronal contributes to AD pathogenesis is unknown. METHODS Using neuron‐specific Abca7 KO mice (n −/− ) or without 5×FAD amyloid model background and post mortem brains, we investigated AD‐related phenotypes through comprehensive approaches including transcriptomics lipidomics. RESULTS Lipidomics analysis detected altered lipid profiles in brains synaptosomes 5×FAD; n compared controls. Transcriptomics profiling revealed that deficiency expression genes pathways related mitochondrial homeostasis apoptosis, particularly excitatory neurons. Consistently, isolated from showed diminished mitochondria respiration reduced synaptic protein levels, which further supported by results human brains. DISCUSSION Our findings reveal plays a critical role important for function survival presence pathology. Highlights Neuronal exacerbates Aβ pathology damage mice. alters brain transcriptomes lipidomes disturbs functions associates

Language: Английский

Citations

1