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 biogenesis and functions in health and disease DOI Open Access

Armella Zadoorian,

Ximing Du, Hongyuan Yang

et al.

Nature Reviews Endocrinology, Journal Year: 2023, Volume and Issue: 19(8), P. 443 - 459

Published: May 23, 2023

Language: Английский

Citations

266
ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias DOI Creative Commons
Yuka A. Martens, Na Zhao, Chia‐Chen Liu

et al.

Neuron, Journal Year: 2022, Volume and Issue: 110(8), P. 1304 - 1317

Published: March 16, 2022

Language: Английский

Citations

215
Solving neurodegeneration: common mechanisms and strategies for new treatments DOI Creative Commons
Lauren K. Wareham, Shane A. Liddelow, Sally Temple

et al.

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

Published: March 21, 2022

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology site disease pathology. To address these and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus the Melza M. Frank Theodore Barr Foundation collaborated to bring together key opinion leaders experts field for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style focused uncovering mechanistic roots promising new catalyzed by goal finding treatments glaucoma, world's leading cause irreversible blindness interest three hosting foundations. Glaucoma, which causes vision loss through degeneration optic nerve, likely shares early cellular molecular events with other diseases central nervous system. Here we major areas overlap between system: neuroinflammation, bioenergetics metabolism, genetic contributions, neurovascular interactions. We summarize important discussion points emphasis research that are most innovative treatment neurodegeneration yet require further development. The is highlighted provides unique opportunities collaboration will lead efforts preventing ultimately loss.

Language: Английский

Citations

196
Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise DOI
Fei Yin

FEBS Journal, Journal Year: 2022, Volume and Issue: 290(6), P. 1420 - 1453

Published: Jan. 8, 2022

Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, a lack of disease‐modifying therapeutics. While the abnormal accumulation lipids was described in very first report AD neuropathology, it not until recent decades that lipid dyshomeostasis became focus research. Clinically, lipidomic metabolomic studies have consistently shown alterations levels various classes emerging early stages brains. Mechanistically, discovery research revealed multifaceted interactions between metabolism key pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, myelin degeneration. In present review, converging evidence defining summarized, followed by discussions on which contributes to pathogenesis modifies risk. Furthermore, lipid‐targeting therapeutic strategies, modification their efficacy stage, ApoE status, metabolic vascular profiles, are reviewed.

Language: Английский

Citations

193
Lipid droplets and cellular lipid flux DOI

Alyssa J. Mathiowetz,

James A. Olzmann

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(3), P. 331 - 345

Published: March 1, 2024

Language: Английский

Citations

87
Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids DOI Creative Commons
Katharina Papsdorf, Jason W. Miklas,

Amir Hosseini

et al.

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(5), P. 672 - 684

Published: May 1, 2023

Abstract Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced Caenorhabditis elegans . upregulate number of fat storage tissues. Increased droplet necessary predicts remaining lifespan. Lipidomics datasets reveal also modify ratio membrane lipids ether lipids—a signature associated with decreased oxidation. In agreement this, decrease oxidation middle-aged individuals. Intriguingly, not only but peroxisome number. A targeted screen identifies genes involved co-regulation peroxisomes, reveals induction both organelles optimal longevity. Our study uncovers homeostasis regulation, opening new avenues interventions delay aging.

Language: Английский

Citations

75
Brain energy metabolism: A roadmap for future research DOI Creative Commons
Caroline Rae, Joseph A. Baur, Karin Borges

et al.

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: 168(5), P. 910 - 954

Published: Jan. 6, 2024

Although we have learned much about how the brain fuels its functions over last decades, there remains still to discover in an organ that is so complex. This article lays out major gaps our knowledge of interrelationships between metabolism and function, including biochemical, cellular, subcellular aspects functional imaging adult brain, as well during development, aging, disease. The focus on unknowns substrates associated transporters, roles insulin lipid droplets, emerging role microglia, mysteries cofactor signaling molecule NAD

Language: Английский

Citations

36
Single-cell mapping of lipid metabolites using an infrared probe in human-derived model systems DOI Creative Commons
Yeran Bai,

Carolina M. Camargo,

Stella M.K. Glasauer

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 8, 2024

Abstract Understanding metabolic heterogeneity is the key to uncovering underlying mechanisms of metabolic-related diseases. Current imaging studies suffer from limitations including low resolution and specificity, model systems utilized often lack human relevance. Here, we present a single-cell platform enable direct lipid metabolism with high specificity in various human-derived 2D 3D culture systems. Through incorporation an azide-tagged infrared probe, selective detection newly synthesized lipids cells tissue became possible, while simultaneous fluorescence enabled cell-type identification complex tissues. In proof-of-concept experiments, were directly visualized human-relevant among different cell types, mutation status, differentiation stages, over time. We identified upregulated progranulin-knockdown induced pluripotent stem their differentiated microglia cells. Furthermore, observed that neurons brain organoids exhibited significantly lower compared astrocytes.

Language: Английский

Citations

27
APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size DOI Creative Commons
Ian A. Windham, Alex E. Powers, Joey V. Ragusa

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(4)

Published: Feb. 9, 2024

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response lipogenesis, apolipoprotein E (APOE) astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic lipid droplets (LDs) via membrane bridges at ER-LD contacts. knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride pulse-chase. This LD size phenotype was rescued by chimeric targets only LDs. Like depletion, APOE4-expressing form small number large enriched triglyceride. Additionally, APOE4 cells exhibit impaired turnover increased sensitivity peroxidation. Our data indicate plays previously unrecognized role as an surface protein regulates composition. causes aberrant composition morphology. study contributes accumulating evidence with large, are sensitized peroxidation, could contribute disease risk.

Language: Английский

Citations

22
The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer’s disease DOI Creative Commons

Xudong Sha,

Jiayuan Lin,

Kexin Wu

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 14, 2025

Abstract Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified aging mouse human brain; however, little is known about formation role lipid droplets microglial neuroinflammation Alzheimer’s disease (AD). Here, we report a striking buildup accumulation 3xTg brain. Moreover, observed significant upregulation PKM2 sterol regulatory element binding protein 1 (SREBP1) levels, which predominantly localized mice. dimerization was necessary for SREBP1 activation lipogenesis droplet-accumulating microglia. RNA sequencing analysis isolated from mice exhibited transcriptomic changes metabolism, innate inflammation, phagocytosis dysfunction; these improved with capsaicin-mediated pharmacological TRPV1 via inhibition reduction activation. Lipid increased mitochondrial injury accompanied impaired mitophagy, abrogated upon Capsaicin also rescued neuronal loss, tau pathology, memory impairment Our study suggests that TRPV1-PKM2-SREBP1 axis regulation metabolism could be therapeutic approach to alleviate consequences AD.

Language: Английский

Citations

3