Lipid rafts: novel therapeutic targets for metabolic, neurodegenerative, oncological, and cardiovascular diseases

Lipids in Health and Disease, Journal Year: 2025, Volume and Issue: 24(1)

Published: April 17, 2025

Lipid rafts are specialized microdomains within cellular membranes enriched with cholesterol and sphingolipids that play key roles in organization, signaling, homeostasis. This review highlights their involvement protein clustering, energy metabolism, oxidative stress responses, inflammation, autophagy, apoptosis. These findings clarify influence on trafficking, adhesion while interacting the extracellular matrix, cytoskeleton, ion channels, making them pivotal progression of various diseases. further addresses contributions to immune including autoimmune diseases, chronic cytokine storms. Additionally, role as entry points for pathogens has been demonstrated, raft-associated receptors being exploited by viruses bacteria increase infectivity evade defenses. Disruptions lipid raft dynamics linked signaling defects, which contribute metabolic, neurodegenerative, cardiovascular underscores potential therapeutic targets, discussing innovations such engineered transplantation. Advances analytical techniques mass spectrometry have expanded our understanding composition dynamics, opening new directions research. By consolidating current insights, we highlight need exploration molecular mechanisms.

Language: Английский

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Molecular and biophysical features of hippocampal “lipid rafts aging” are modified by dietary n‐3 long‐chain polyunsaturated fatty acids

Aging Cell, Journal Year: 2023, Volume and Issue: 22(8)

Published: May 30, 2023

Abstract “Lipid raft aging” in nerve cells represents an early event the development of aging‐related neurodegenerative diseases, such as Alzheimer's disease. Lipid rafts are key elements synaptic plasticity, and their modification with aging alters interactions distribution signaling molecules, glutamate receptors ion channels involved memory formation, eventually leading to cognitive decline. In present study, we have analyzed, vivo, effects dietary supplementation n‐3 LCPUFA on lipid structure, membrane microviscosity, domain organization, partitioning ionotropic metabotropic hippocampal raffs female mice. The results revealed several signatures “lipid old mice fed control diets, consisting depletion LCPUFA, unsaturation, along increased levels saturates, plasmalogens, sterol esters, well altered relevant indexes. These changes were paralleled by microviscosity raft/non‐raft (R/NR) AMPA‐R mGluR5. Administration diet caused partial reversion fatty acid alterations found aged returned values young animals. Paralleling these findings, accumulated mGluR5, NMDA‐R, ASIC2, R/NR proportions, which collectively indicate plasticity. Unexpectedly, this also modified lipidome dimension rafts, redistribution acid‐sensing likely modulating functionality formation reluctance age‐associated

Language: Английский

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Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer’s Disease

Biomolecules, Journal Year: 2024, Volume and Issue: 14(11), P. 1362 - 1362

Published: Oct. 26, 2024

Aging induces complex changes in the lipid profiles across different areas of brain. These can affect function brain cells and may contribute to neurodegenerative diseases such as Alzheimer's disease. Research shows that while overall profile human remains quite steady throughout adulthood, specific occur with age, especially after age 50. include a slow decline total content shifts composition fatty acids, particularly glycerophospholipids cholesterol levels, which vary depending on region. Lipid rafts play crucial role maintaining membrane integrity facilitating cellular signaling. In context disease, have been associated development For example, alterations raft lead increased accumulation amyloid β (Aβ) peptides, contributing neurotoxic effects. droplets store neutral lipids are key for energy metabolism. As organisms dynamics change, evidence suggesting metabolic activity over time. This reduced an imbalance synthesis mobilization, processes. model like Drosophila, studies shown metabolism be influenced by diet insulin signaling pathways, balance. The interplay between metabolism, oxidative stress, inflammation is critical aging peroxidation, consequence formation reactive aldehydes further damage neurons. Inflammatory processes also disrupt pathology AD. Consequently, oxidized integrity, influencing pathways involved neuronal survival function.

Language: Английский

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Non-canonical pathways associated to Amyloid beta and tau protein dyshomeostasis in Alzheimer’s disease: A narrative review

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 102, P. 102578 - 102578

Published: Nov. 13, 2024

Alzheimer's Disease (AD) is the most common form of dementia among elderly people. This disease imposes a significant burden on healthcare system, society, and economy due to increasing global aging population. Current trials with drugs or bioactive compounds aimed at reducing cerebral Amyloid beta (Aβ) plaques tau protein neurofibrillary tangles, which are two main hallmarks this devastating neurodegenerative disease, have not provided results in terms their neuropathological outcomes nor met expected clinical end-points. Ageing, genetic environmental risk factors, along different symptoms suggest that AD complex heterogeneous disorder multiple interconnected pathological pathways rather than single entity. In present review, we highlight discuss various non-canonical, Aβ-independent mechanisms, like gliosis, unhealthy dietary intake, lipid sugar signaling, cerebrovascular damage contribute onset development AD. We emphasize challenging traditional "amyloid cascade hypothesis" may improve our understanding age-related syndrome help fight progressive cognitive decline

Language: Английский

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Correlations between omega-3 fatty acids and inflammatory/glial abnormalities: the involvement of the membrane and neurotransmitter dysfunction in schizophrenia

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Oct. 23, 2023

Introduction Macrophages or T-lymphocytes triggered inflammation and, consequently, activated glial cells may contribute to neuroinflammation and neurotransmitter dysfunction in schizophrenia (SZ), while omega(n)-3 polyunsaturated fatty acids (PUFAs) can attenuate some SZ symptoms through anti-inflammatory effects. However, the correlations between macrophage/T-lymphocyte-produced cytokines glia phenotypes, inflammatory status PUFAs composition, function, n-3 abnormality are unclear. Methods Changes T-helper (h) patterns, peripheral macrophage/glial markers, profile, membrane fluidity, functions were evaluated patients ( n = 50) healthy controls 30) using ELISA, gas chromatography, fluorescence anisotropy techniques, HPLC, respectively. Results Compared control, blood lymphocyte proliferation, concentration of macrophage/microglia phenotype M1 including IL-1β, TNF-α (Th1) IL-6 (Th2), astrocyte A1 marker S100β was significantly increased, IL-17 contents, n-3/n-6 ratio, fluidity (FLU) decreased SZ. Moreover, increased DA HVA, 5-HT NE, their metabolites appeared negative A2 Brain-Derived Neurotrophic Factor (BDNF) EPA IL-1β FLU 5HIAA, positive 5-HIAA DHA found Discussion These findings showed (1) no clear Th pattern, but pro-inflammatory-dominant immunity occurred; (2) pro-inflammatory pattern result microglia phenotype; (3) related PUFA dysfunctional systems

Language: Английский

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AozC, a zn(II)2Cys6 transcription factor, negatively regulates salt tolerance in Aspergillus oryzae by controlling fatty acid biosynthesis

Microbial Cell Factories, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 7, 2025

In the soy sauce fermentation industry, Aspergillus oryzae (A. oryzae) plays an essential role and is frequently subjected to high salinity levels, which pose a significant osmotic stress. This environmental challenge necessitates activation of stress response mechanisms within fungus. The Zn(II)2Cys6 family transcription factors, known for their zinc binuclear cluster-containing proteins, are key regulators in fungi, modulating various cellular functions such as adaptation metabolic pathways. Overexpression AozC decreased growth rates presence salt, while its knockdown enhanced growth, number spores, biomass, particularly under conditions 15% salt concentration, doubling these metrics compared wild type. Conversely, via RNA interference significantly spore density dry stress, where parameters were markedly improved over type strain. Moreover, overexpression led downregulation FAD2 gene, pivotal enzyme biosynthesis unsaturated fatty acids (UFAs), preserving cell membrane fluidity integrity saline conditions. Transcriptome profiling further exposed influence on regulation UFA modulation critical Notably, regulatory mitogen-activated protein kinase (MAPK) signaling ABC transporters pathways was highlighted, underscoring significance balance endoplasmic reticulum homeostasis. These findings collectively indicate that negative regulator tolerance A. oryzae. research suggest acts modulates acid results provide insights into

Language: Английский

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Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimers disease in humans

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Abstract As the principal lipid transporter in human brain, apolipoprotein E (ApoE) is tasked with transport and protection of highly vulnerable lipids required to support remodel neuronal membranes, a process that dependent on ApoE receptors. Human APOE allele variants encode proteins differing only number cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 ApoE4 [0 Cys]) comprise strongest genetic risk factor for sporadic Alzheimer’s disease (AD); however, specific molecular feature(s) resultant mechanisms underlie these isoform-dependent effects are unknown. One signature feature Cys capacity form disulfide (Cys-Cys) bridges, which bridge-linked dimers multimers. Here we propose overarching hypothesis super-ability (for ApoE2), intermediate ability ApoE3) or inability ApoE4) lipid-protecting intermolecular central determinant accounting disparate alleles AD amyloid-β Tau pathologies humans. We posit presence abundance ApoE2 respectively, conceal protect transported by from peroxidation enabling formation homo-dimers/multimers heteromeric complexes such as ApoE-ApoJ ApoE-ApoD. thus bridges makes ApoE4-containing lipoproteins uniquely its downstream consequences. Consistent our model, found brain-enriched polyunsaturated fatty acid-containing phospholipids induce disulfide-dependent dimerization multimerization (but not ApoE4). By contrast, incubation peroxidation-resistant DMPC cholesterol alone had minimal dimerization. These novel concepts findings integrated into unifying model implicating ApoE-containing lipoproteins, consequent receptor-ligand disruption, initiating events ultimately lead Highlights (AD) differ Cys⟶Arg Despite 30 years inquiry, linking remain unknown PUFA-phospholipids induced bridge hypothesize explain allele-dependent risks

Language: Английский

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Sex difference in TRPM3 channel functioning in nociceptive and vascular systems: an emerging target for migraine therapy in females?

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 24, 2025

Transient Receptor Potential Melastatin 3 (TRPM3) channels are Ca2+ permeable ion that act as polymodal sensors of mechanical, thermal, and various chemical stimuli. TRPM3 highly expressed in the trigeminovascular system, including trigeminal neurons vasculature. Their presence dural afferents suggests they potential triggers migraine pain, which is originating from meningeal area. This area densely innervated by autonomous nerves contain major mediator calcitonin gene-related peptide (CGRP) peptidergic nerve fibers. Co-expression CGRP receptors a interplay between both signalling systems. Compared to other members TRP family, have high sensitivity sex hormones endogenous neurosteroid pregnenolone sulfate (PregS). The predominantly female estrogen progesterone, levels drop during menses, natural inhibitors channels, while PregS known agonist these channels. A decrease hormone has also been suggested trigger for attacks menstrually-related migraine. Notably, there remarkable difference TRPM3-mediated effects nociceptive In line with this, relaxation human isolated arteries induced activation greater females. Additionally, sex-dependent vasodilatory responses seem be influenced age-related hormonal changes, could contribute differences pathology. Consistent observations, sensory firing much more prominently than male mouse meninges, suggesting pain processing patients may differ. Overall, combined TRPM3-related neuronal vascular mechanisms provide possible explanation higher prevalence even severe quality narrative review summarizes recent data on roles pathophysiology, signalling, highlights prospects translational therapies targeting particular relevance women

Language: Английский

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Two‐Sample Mendelian Randomization Analyses Identified Lipid Species Associated With Intracranial Aneurysm Formation

Brain and Behavior, Journal Year: 2025, Volume and Issue: 15(3)

Published: March 1, 2025

ABSTRACT Objectives Intracranial aneurysm (IA) poses a significant health risk, and its formation involves various factors, including lipid metabolism, while former research only focused on the standard lipid. The purpose of this study is to explore 179 variants' impact unruptured intracranial aneurysms (uIA). Materials Methods Utilizing GWAS data for lipids uIAs, MR analyses were employed with pleiotropy, heterogeneity, sensitivity tests. Reverse then conducted. Results revealed seven associated uIAs: TAG (51:3). SE (27:1/16:1), PC (18:2_18:2), (48:1), (48:2), (51:3) identified as uIA risk (27:1/18:1) SM (d34:0) exhibited protective effects. analysis showed no bidirectional causal relationships. Conclusions This identifies specific variants causally linked shedding light their roles in IA formation. These findings contribute future assessment potential therapeutic interventions.

Language: Английский

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HYPOTHESIS: Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer's disease in humans

Prostaglandins Leukotrienes and Essential Fatty Acids, Journal Year: 2025, Volume and Issue: unknown, P. 102681 - 102681

Published: April 1, 2025

Language: Английский

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