Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects DOI Creative Commons
Femke M. Feringa, Rik van der Kant

Frontiers in Aging Neuroscience, Год журнала: 2021, Номер 13

Опубликована: Июнь 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.

Язык: Английский

Dynamics and functions of lipid droplets DOI
James A. Olzmann, Pedro Carvalho

Nature Reviews Molecular Cell Biology, Год журнала: 2018, Номер 20(3), С. 137 - 155

Опубликована: Дек. 6, 2018

Язык: Английский

Процитировано

2060
The Science and Translation of Lactate Shuttle Theory DOI Creative Commons
George A. Brooks

Cell Metabolism, Год журнала: 2018, Номер 27(4), С. 757 - 785

Опубликована: Апрель 1, 2018

Язык: Английский

Процитировано

978
Lactate in the brain: from metabolic end-product to signalling molecule DOI
Pierre J. Magistretti, Igor Allaman

Nature reviews. Neuroscience, Год журнала: 2018, Номер 19(4), С. 235 - 249

Опубликована: Март 8, 2018

Язык: Английский

Процитировано

955
ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease DOI Creative Commons
Dominic S. A. Simpson, Peter L. Oliver

Antioxidants, Год журнала: 2020, Номер 9(8), С. 743 - 743

Опубликована: Авг. 13, 2020

Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation neuronal damage result in the activation disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation reactive oxygen species (ROS) generation. However, mechanisms linking OS have not been well-defined; thus targeting these cells for clinical benefit has possible. In microglia, ROS generated primarily by NADPH oxidase 2 (NOX2) NOX2 is associated DAMP signalling, amyloid plaque deposition, especially cerebrovasculature. Additionally, originating from both NOX mitochondria may act second messengers propagate immune activation; intracellular signalling underlie excessive OS. Targeting key kinases inflammatory response could cease promote tissue repair. Expression antioxidant proteins dehydrogenase 1 (NQO1), promoted transcription factor Nrf2, which functions control limit Lipid droplet accumulating (LDAM) also represent double-edged sword neurodegenerative sequestering peroxidised lipids non-pathological ageing but becoming dysregulated pro-inflammatory disease. We suggest that future studies should focus on targeted manipulation understand driving inflammatory-related activation. Finally, we discuss recent evidence therapeutic target identification be unbiased founded relevant pathophysiological assays discovery translatable anti-inflammatory therapeutics.

Язык: Английский

Процитировано

728
Lactate metabolism in human health and disease DOI Creative Commons
Xiaolu Li, Yanyan Yang, Bei Zhang

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Сен. 1, 2022

Abstract The current understanding of lactate extends from its origins as a byproduct glycolysis to role in tumor metabolism, identified by studies on the Warburg effect. shuttle hypothesis suggests that plays an important bridging signaling molecule coordinates among different cells, organs and tissues. Lactylation is posttranslational modification initially reported Professor Yingming Zhao’s research group 2019. Subsequent confirmed lactylation vital component function involved proliferation, neural excitation, inflammation other biological processes. An indispensable substance for various physiological cellular functions, regulatory aspects energy metabolism signal transduction. Therefore, comprehensive review summary presented clarify disease provide reference direction future research. This offers systematic overview homeostasis roles pathological processes, well effects diseases, particularly cancer.

Язык: Английский

Процитировано

670
Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity DOI Creative Commons
Maria S. Ioannou, Jesse Jackson, Shu‐Hsien Sheu

и другие.

Cell, Год журнала: 2019, Номер 177(6), С. 1522 - 1535.e14

Опубликована: Май 1, 2019

Язык: Английский

Процитировано

533
Lactate as a fulcrum of metabolism DOI Creative Commons
George A. Brooks

Redox Biology, Год журнала: 2020, Номер 35, С. 101454 - 101454

Опубликована: Фев. 9, 2020

Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that L-enantiomer lactate anion is formed under fully aerobic conditions and utilized continuously diverse cells, tissues, organs at whole-body level. By shuttling between producer (driver) consumer (recipient) cells fulfills least three purposes: 1] a major energy source for mitochondrial respiration; 2] gluconeogenic precursor; 3] signaling molecule. Working by mass action, cell redox regulation, allosteric binding, reprogramming chromatin lactylation lysine residues on histones, has influences substrate partitioning. The physiological range tissue [lactate] 0.5-20 mM cellular Lactate/Pyruvate ratio (L/P) can from 10 >500; these changes during exercise other stress-strain responses dwarf metabolic signals magnitude span. Hence, dynamics have rapid short- long-term effects control systems. inhibiting lipolysis adipose via HCAR-1, fatty acid uptake malonyl-CoA CPT1, controls Repeated exposure regular results expression regulatory enzymes glycolysis respiration. Lactate fulcrum regulation vivo.

Язык: Английский

Процитировано

486
Amyloid-β-independent regulators of tau pathology in Alzheimer disease DOI
Rik van der Kant, Lawrence S.B. Goldstein, Rik Ossenkoppele

и другие.

Nature reviews. Neuroscience, Год журнала: 2019, Номер 21(1), С. 21 - 35

Опубликована: Ноя. 28, 2019

Язык: Английский

Процитировано

452
Lipid Droplets in Cancer: Guardians of Fat in a Stressful World DOI Creative Commons
Toni Petan, Eva Jarc Jovičić,

Maida Jusović

и другие.

Molecules, Год журнала: 2018, Номер 23(8), С. 1941 - 1941

Опубликована: Авг. 3, 2018

Cancer cells possess remarkable abilities to adapt adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity acquire extracellular lipids the plasticity of mechanisms for intracellular lipid synthesis, mobilisation, recycling. Lipid droplets, cytosolic fat storage organelles present in most from yeast men, are emerging as major regulators metabolism, trafficking, signalling various tissues exposed stress. biogenesis is induced by they accumulate cancers. droplets act switches that coordinate trafficking consumption different purposes cell, such energy production, protection against or membrane rapid cell growth. They sequester toxic lipids, fatty acids, cholesterol ceramides, thereby preventing lipotoxic damage engage a complex relationship with autophagy. Here, we focus stress-induced droplet biogenesis; roles nutrient, lipotoxic, stress; between The recently discovered principles biology can improve our understanding govern cancer adaptability resilience

Язык: Английский

Процитировано

308
A gene-specific T2A-GAL4 library for Drosophila DOI Creative Commons
Pei-Tseng Lee, Jonathan Zirin, Oguz Kanca

и другие.

eLife, Год журнала: 2018, Номер 7

Опубликована: Март 22, 2018

We generated a library of ~1000 Drosophila stocks in which we inserted construct the intron genes allowing expression GAL4 under control endogenous promoters while arresting transcription with polyadenylation signal 3' GAL4. This allows numerous applications. First, ~90% insertions essential cause severe loss-of-function phenotype, an effective way to mutagenize genes. Interestingly, 12/14 chromosomes engineered through CRISPR do not carry second-site lethal mutations. Second, 26/36 (70%) tested are rescued single UAS-cDNA construct. Third, phenotypes associated many can be reverted by excision UAS-flippase. Fourth, driven UAS-GFP/RFP reports tissue and cell-type specificity gene high sensitivity. report hundreds previously reported. Finally, cassettes replaced GFP or any DNA. These comprise powerful resource for assessing function.

Язык: Английский

Процитировано

294