Lipid droplet biogenesis and functions in health and disease

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

Published: May 23, 2023

Language: Английский

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Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

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

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Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: June 24, 2021

While the central nervous system compromises 2% of our body weight, it harbors up to 25% body's cholesterol. Cholesterol levels in brain are tightly regulated for physiological function, but mounting evidence indicates that excessive cholesterol accumulates Alzheimer's disease (AD), where may drive AD-associated pathological changes. This seems especially relevant late-onset AD, as several major genetic risk factors functionally associated with metabolism. In this review we discuss different systems maintain metabolism healthy brain, and how dysregulation these processes can lead, or contribute to, disease. We will also AD-risk genes might impact downstream AD pathology. Finally, address outstanding questions field recent technical advances CRISPR/Cas9-gene editing induced pluripotent stem cell (iPSC)-technology aid study problems.

Language: Английский

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Lipid droplets in the nervous system

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(7)

Published: June 21, 2021

Lipid droplets are dynamic intracellular lipid storage organelles that respond to the physiological state of cells. In addition controlling cell metabolism, they play a protective role for many cellular stressors, including oxidative stress. Despite prior descriptions appearing in brain as early century ago, only recently has cells found begun be understood. droplet functions have now been described nervous system context development, aging, and an increasing number neuropathologies. Here, we review basic mechanisms formation, turnover, function discuss how these enable different types under healthy pathological conditions.

Language: Английский

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GBA Variants and Parkinson Disease: Mechanisms and Treatments

Cells, Journal Year: 2022, Volume and Issue: 11(8), P. 1261 - 1261

Published: April 8, 2022

The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in gene, making it numerically most important genetic risk factor Parkinson disease (PD). Clinically, GBA-associated is identical to sporadic PD, aside from earlier age at onset (AAO), more frequent cognitive impairment and rapid progression. Mutations can be associated with loss- gain-of-function mechanisms. A key hallmark presence intraneuronal proteinaceous inclusions named Lewy bodies, are made up primarily alpha-synuclein. may lead loss GCase activity dysfunction, impair alpha-synuclein metabolism. Models deficiency demonstrate dysfunction autophagic-lysosomal pathway subsequent accumulation This also aberrant lipid metabolism, including glycosphingolipids, glucosylceramide glucosylsphingosine. Certain cause misfolded retained endoplasmic reticulum (ER), activating stress responses unfolded protein response (UPR), contribute neurodegeneration. In addition these mechanisms, a has been mitochondrial neuroinflammation, implicated pathogenesis PD. review discusses pathways GBA-PD highlights potential treatments act target prevent

Language: Английский

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112196 - 112196

Published: March 1, 2023

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept immunometabolism. Here, we combined bulk, single-cell, spatial transcriptomics cell-specific spatially resolved analyses in mice expressing human APOE to systematically address role across age, neuroinflammation, AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes APOE4 glial transcriptome, specifically subsets metabolically distinct microglia enriched brain during aging or following an inflammatory challenge. display increased Hif1α expression disrupted tricarboxylic acid (TCA) cycle are inherently pro-glycolytic, while mass spectrometry imaging highlight E4-specific response amyloid characterized by widespread alterations lipid metabolism. Taken together, our emphasize central for regulating microglial immunometabolism provide valuable, interactive resources discovery validation research.

Language: Английский

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A neuron–glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(4), P. 666 - 678

Published: Feb. 15, 2024

Abstract Sleep is thought to be restorative brain energy homeostasis, but it not clear how this achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation dependent on prior wake requires the APOE orthologs NLaz GLaz, which mediate neuron–glia transfer. In turn, full night sleep required for clearance, oxidative recovery maximal neuronal mitophagy. Knockdown causes stress accumulate in neurons, integrity protein, Drp1, accumulation. These data suggest neurons avoid damage during by using mitophagy passing form lipids. propose metabolic between reflects fundamental function relevant homeostasis.

Language: Английский

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Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration

Science Advances, Journal Year: 2023, Volume and Issue: 9(10)

Published: March 8, 2023

Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia the brain of old C57BL/6 mice (>18 months old) demonstrate that comparison to young mice, one-third are AF, characterized profound changes lipid iron content, phagocytic activity, oxidative stress. Pharmacological depletion eliminated AF following repopulation reversed microglial dysfunction. Age-related neurological deficits neurodegeneration after traumatic injury (TBI) were attenuated lacking microglia. Furthermore, increased lysosomal burden, accumulation persisted for up 1 year TBI, modified APOE4 genotype, chronically driven phagocyte-mediated Thus, may reflect a pathological state aging associated phagocytosis neurons myelin inflammatory can be further accelerated TBI.

Language: Английский

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Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(6), P. 1351 - 1370.e8

Published: April 23, 2024

Language: Английский

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Brain energy metabolism: A roadmap for future research

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

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