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

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

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The role of mitochondrial dynamics in cerebral ischemia-reperfusion injury

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 162, С. 114671 - 114671

Опубликована: Апрель 8, 2023

Stroke is one of the leading causes death and long-term disability worldwide. More than 80 % strokes are ischemic, caused by an occlusion cerebral arteries. Without question, restoration blood supply as soon possible first therapeutic strategy. Nonetheless paradoxically, reperfusion can further aggravate injury through a series reactions known ischemia-reperfusion (CIRI). Mitochondria play vital role in promoting nerve survival neurological function recovery mitochondrial dysfunction considered characteristics CIRI. Neurons often die due to oxidative stress imbalance energy metabolism following CIRI, there strong association with dysfunction. Altered dynamics reaction stress. Mitochondrial refers maintenance integrity, distribution, size mitochondria well their ability resist external stimuli continuous cycle fission fusion. Therefore, improving means treating This review discusses relationship between CIRI emphasizes potential approach improve prognosis

Язык: Английский

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Modulation of Mitochondria–Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS associated with alterations lipid metabolism. As its regulation occurs mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) emerging as crucial factor MAM formation and metabolism control. Using the MERLIN biosensor high-throughput screening within EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated cholesterol trafficking decreased an patient-derived cell model, this restored after treatment MERC modulator 24. Electron microscopy revealed compound 24 increases MERCs, promotes droplet formation, restores mitochondrial cristae. Overall, brain-permeable modulator, 24, may serve valuable pharmacological tool for studying function holds potential vivo studies other dysfunction diseases.

Язык: Английский

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Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Авг. 25, 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder that one of the most devastating and widespread diseases worldwide, mainly affecting aging population. One key factors contributing to AD-related neurotoxicity production aggregation amyloid β (Aβ). Many studies have shown ability Aβ bind cell membrane disrupt its structure, leading death. Because damage affects different parts brain differently, it seems likely not only but also nature interface with which interacts, helps determine final neurotoxic effect. cholesterol dominant component plasma membrane, plays an important role in Aβ-induced toxicity. Elevated levels their regulation by statins been be influencing progression neurodegeneration. However, data from many has both neuroprotective aggravating effects relation development AD. In this review, we attempt summarize recent findings on toxicity mediated binding pathogenesis AD consider broader context lipid composition membranes.

Язык: Английский

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Intracellular Cholesterol Synthesis and Transport

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Март 21, 2022

Cholesterol homeostasis is related to multiple diseases in humans, including cardiovascular disease, cancer, and neurodegenerative hepatic diseases. The cholesterol levels cells are balanced dynamically by uptake, biosynthesis, transport, distribution, esterification, export. In this review, we focus on de novo synthesis, synthesis regulation, intracellular trafficking. addition, the progression of lipid transfer proteins (LTPs) at contact sites between organelles considered.

Язык: Английский

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Probiotics Interact With Lipids Metabolism and Affect Gut Health

Frontiers in Nutrition, Год журнала: 2022, Номер 9

Опубликована: Май 31, 2022

Probiotics have attracted much attention due to their ability modulate host intestinal microbe, participate in nutrient metabolism or immunomodulatory. Both inflammatory bowel disease (IBD) and cancer are digestive system disease, which become a global public health problem unclear etiology, difficult cure, repeated attacks. Disturbed gut microbiota abnormal lipid would increase the risk of inflammation. However, link between metabolism, probiotics, IBD is unclear. In this review, we found that different lipids derivatives effects on microbes. ω-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid, eicosapentaenoic resolvin E1, D can inhibit oxidative stress reactive oxygen species activate NFκB MAPk pathway. While ω-6 PUFAs linoleic acid arachidonic be derived into leukotrienes prostaglandins, will aggravate IBD. Cholesterol converted bile promote absorption affect microbial survival colonization. At same time, it affected by salt hydrolase regulate blood lipids. Low denstiy lipoprotein (LDL) easily oxidized LDL, thereby promoting inflammation, while high (HDL) has opposite effect. compete with microorganisms for nutrients ecological sites thus structure microbiota. Moreover, short chain acids, hydrolase, superoxide dismutase, glutathione, etc. conclusion, probiotics directly indirectly involved impact IBD, provides possibility explore role improving health.

Язык: Английский

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Brain metabolism in Alzheimer’s disease: biological mechanisms of exercise

Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)

Опубликована: Июнь 26, 2023

Alzheimer's disease (AD) is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation multiple adverse factors, accompanied dysregulation numerous intracellular signaling molecular pathways in the brain. At cellular levels, neuronal milieu AD brain exhibits metabolic abnormalities, compromised bioenergetics, impaired lipid metabolism, reduced overall capacity, which lead to abnormal neural network activity neuroplasticity, thus accelerating formation extracellular senile plaques neurofibrillary tangles. The current absence effective pharmacological therapies for points urgent need investigate benefits non-pharmacological approaches such as physical exercise. Despite evidence that regular can improve dysfunction state, inhibit different pathophysiological associated with AD, influence pathological process exert protective effect, there no clear consensus on specific biological mechanisms underlying advantages Here, we review how exercise improves crucial processes disorders including glucose Aβ metabolism transport, iron tau pathology. How states health also presented. A better knowledge neurophysiological contribute development novel drugs improvement interventions.

Язык: Английский

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CD11c+ microglia promote white matter repair after ischemic stroke

Cell Death and Disease, Год журнала: 2023, Номер 14(2)

Опубликована: Фев. 24, 2023

Abstract Ischemic stroke leads to white matter damage and neurological deficits. However, the characteristics of injury repair after are unclear. Additionally, precise molecular communications between microglia during rehabilitation phase remain elusive. In this current study, MRI DTI scan immunofluorescence staining were performed trace in mouse transient middle cerebral artery occlusion (tMCAO) model. We found that most serious was on Day 7 ischemic stroke, then it recovered gradually from 30. Parallel recovery, we observed centered around damaged myelin sheath swallowed debris areas. Then, hemisphere sorted by flow cytometry for RNA sequencing subpopulation analysis. CD11c + increased 30, demonstrating high phagocytotic capabilities, myelin-supportive genes, lipid metabolism associated genes. population partly depleted stereotactic injecting rAAV2/6M-taCasp3 (rAAV2/6M-CMV-DIO-taCasp3-TEVp) into CD11c-cre mice. Selective depletion disrupted repair, oligodendrocyte maturation, functional recovery Rotarod test, Adhesive Removal Morris Water Maze test. These findings suggest spontaneous occurs while play critical roles restorative progress.

Язык: Английский

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Cholesterol Metabolism in Aging and Age-Related Disorders

Annual Review of Neuroscience, Год журнала: 2023, Номер 46(1), С. 59 - 78

Опубликована: Июль 10, 2023

All mammalian cell membranes contain cholesterol to maintain membrane integrity. The transport of this hydrophobic lipid is mediated by lipoproteins. Cholesterol especially enriched in the brain, particularly synaptic and myelin membranes. Aging involves changes sterol metabolism peripheral organs also brain. Some those alterations have potential promote or counteract development neurodegenerative diseases during aging. Here, we summarize current knowledge general principles humans mice, most widely used model organism biomedical research. We discuss that occur aged brain highlight recent developments type-specific fast-growing research field aging age-related diseases, focusing on Alzheimer's disease. propose handling interplay between types critically influence disease processes.

Язык: Английский

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Metabolic perspective of astrocyte dysfunction in Alzheimer's disease and type 2 diabetes brains

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 158, С. 114206 - 114206

Опубликована: Янв. 5, 2023

The term type III diabetes (T3DM) has been proposed for Alzheimer's disease (AD) due to the shared molecular and cellular features between 2 (T2DM) insulin resistance-associated memory deficits cognitive decline in elderly individuals. Astrocytes elicit neuroprotective or deleterious effects AD progression severity. Patients with T2DM are at a high risk of impairment, targeting astrocytes might be promising alleviating neurodegeneration diabetic brain. Recent studies focusing on cell-specific activities brain have revealed important role metabolism (e.g., glucose metabolism, lipid metabolism), neurovascular coupling, synapses, synaptic plasticity. In this review, we discuss how their dysfunction result multiple pathological clinical from metabolic perspective potential comorbid mechanism these two diseases astrocytes.

Язык: Английский

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