Exosomes enriched with miR-124-3p show therapeutic potential in a new microfluidic triculture model that recapitulates neuron–glia crosstalk in Alzheimer’s disease DOI Creative Commons

Artemizia Évora,

Gonçalo Garcia,

Ana Rubi

и другие.

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 12, 2025

Background Alzheimer’s disease (AD), a complex neurodegenerative associated with ageing, is the leading cause of dementia. Few people early AD are eligible for novel Food and Drug Administration (FDA)-approved drug treatments. Accordingly, new tools diagnosis markers required to predict subtypes, individual stages, most suitable personalized treatment. We previously demonstrated that regulation microRNA (miR)-124 crucial proper neuronal function microglia reshaping in human cell models. Objective The aim this study was develop an efficient miR-124-3p-loaded exosome strategy validate its therapeutic potential using multi-compartment microfluidic device neuron–glia recapitulates age-AD pathological features. Methods results Using cortical from mouse pups, separated glial mixed cultures maintained 2 days vitro (stressed microglia), we tested effects SH-SY5Y-derived exosomes loaded miR-124-3p mimic either by their direct transfection Exo-Fect™ (ET124) or isolation secretome miR-124 transfected cells (CT124). ET124 revealed better delivery effciency higher potent improving stressed status than CT124. Tricultures SH-SY5Y neuroblastoma (SH- WT ) were established presence line (HMC3) immortalized astrocytes (IM-HA) tricompartmentalized devices. Replacement SH- those APP695 SWE tricultures addition low doses hydrogen peroxide used simulate late-onset AD. system mimicked AD-associated neurodegeneration neuroinflammation processes. Notably, exhibited neuroprotective properties across three types model preventing apoptosis neurite deficits, redirecting microglial profiles towards steady state, attenuating inflammatory miRNA fingerprints astrocyte reactivity. Conclusion To best our knowledge, first supporting neuro- immunoprotective miR-124-engineered triculture platform, recapitulating age-related susceptibility Our offers medicines patient subtypes.

Язык: Английский

Neuroinflammation in Alzheimer disease DOI
Wiesje M. van der Flier, Wiesje M. van der Flier,

Frank Jessen

и другие.

Nature reviews. Immunology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Язык: Английский

Процитировано

34

Redox regulation: mechanisms, biology and therapeutic targets in diseases DOI Creative Commons
Bowen Li, Hui Ming, Siyuan Qin

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Язык: Английский

Процитировано

5

Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications DOI Creative Commons
Sijia He, Ziying Xu, Xianlin Han

и другие.

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 27, 2025

Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to involvement of lipid dysregulation in development AD. Nevertheless, precise lipidomic landscape and mechanistic roles lipids pathology remain poorly understood. This review aims highlight significance lipidomics lipid-targeting approaches diagnosis We summarized connection between human brain AD at both genetic species levels. briefly introduced technologies discussed potential challenges areas future advancements field for research. To elucidate central role converging multiple pathological aspects AD, we reviewed current knowledge on interplay major features, including amyloid beta, tau, neuroinflammation. Finally, assessed progresses obstacles lipid-based therapeutics proposed strategies leveraging

Язык: Английский

Процитировано

4

Lipid droplets in central nervous system and functional profiles of brain cells containing lipid droplets in various diseases DOI Creative Commons

Longxiao Zhang,

Yunfei Zhou, Zhongbo Yang

и другие.

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Янв. 13, 2025

Lipid droplets (LDs), serving as the convergence point of energy metabolism and multiple signaling pathways, have garnered increasing attention in recent years. Different cell types within central nervous system (CNS) can regulate to generate or degrade LDs response diverse pathological stimuli. This article provides a comprehensive review on composition CNS, their generation degradation processes, interaction mechanisms with mitochondria, distribution among different types, roles played by these cells-particularly microglia astrocytes-in various prevalent neurological disorders. Additionally, we also emphasize paradoxical role post-cerebral ischemia inflammation explore potential underlying mechanisms, aiming identify novel therapeutic targets for this disease.

Язык: Английский

Процитировано

3

Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress DOI
Lindsey D. Goodman, Isha Ralhan,

Xin Li

и другие.

Nature Neuroscience, Год журнала: 2024, Номер 27(10), С. 1918 - 1933

Опубликована: Авг. 26, 2024

Язык: Английский

Процитировано

12

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4 DOI
Femke M. Feringa,

Sascha J. Koppes-den Hertog,

Lian Wang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 3, 2024

Abstract Lipid changes in the brain have been implicated many neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named Neurolipid Atlas, that pre-populated with novel human, mouse isogenic induced pluripotent stem cell (iPSC)-derived lipidomics for different diseases. We show iPSC-derived neurons, microglia astrocytes display distinct lipid profiles recapitulate vivo lipotypes. Leveraging multiple datasets, AD risk gene ApoE4 drives cholesterol ester (CE) accumulation human recapitulating CE measured brain. Multi-omic interrogation of revealed plays major role astrocyte interferon-dependent pathways such as immunoproteasome histocompatibility complex (MHC) class I antigen presentation. through enhanced esterification suppresses immune activation astrocytes. Our commons, available at neurolipidatlas.com, provides user-friendly tool knowledge base better understanding dyshomeostasis

Язык: Английский

Процитировано

11

The circular RNA circbabo(5,6,7,8S) regulates lipid metabolism and neuronal integrity via TGF-β/ROS/JNK/SREBP signaling axis in Drosophila DOI Creative Commons
Jie Sheng, Xuemei Zhang, Weihong Liang

и другие.

BMC Biology, Год журнала: 2025, Номер 23(1)

Опубликована: Март 5, 2025

Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation LDs nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) new class non-coding regulatory widely expressed eukaryotes. However, only subset has been functionally characterized. Here, we identified characterized circular RNA circbabo(5,6,7,8S) regulates lipogenesis neuronal integrity Drosophila melanogaster. derived from babo locus encodes type I receptor for transforming growth factor β (TGF-β). Depletion flies causes elevated droplet accumulation, progressive photoreceptor cell loss shortened lifespan, phenotypes rescued by restoring expression. In addition, RNA-seq epistasis analyses reveal these abnormalities caused aberrant activation SREBP signaling pathway. Furthermore, circbabo(5,6,7,8S)-depleted tissues display enhanced TGF-β pathway compromised mitochondrial function, resulting upregulation reactive oxygen species (ROS). Moreover, provide evidence protein circbabo(5,6,7,8S)-p, inhibits interfering assembly babo/put heterodimer complex. Lastly, show dysregulation ROS/JNK/SREBP cascade responsible LD neurodegeneration, lifespan elicited depletion. Our study demonstrates physiological protein-coding circRNA regulating metabolism integrity.

Язык: Английский

Процитировано

1

Lipid Droplets: Emerging therapeutic targets for age-related metabolic diseases DOI

Zheying Ma,

Shou Pan,

Yaming Yang

и другие.

Ageing Research Reviews, Год журнала: 2025, Номер unknown, С. 102758 - 102758

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

1

Exploring the link between dystrophic microglia and the spread of Alzheimer's neuropathology DOI
Ryan K. Shahidehpour, Peter T. Nelson, Yuriko Katsumata

и другие.

Brain, Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Abstract Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease progression, but details of the disease-driving influence are poorly understood. Microglial cells can be parsed into subtypes based on their histological appearance. One subtype microglia, termed dystrophic is characterized structurally by fragmented processes cytoplasmic decay, presence has been associated with ageing neurodegeneration. Recent studies suggest interaction between tau proteins amyloid-β might induce changes potentially linking pathologies to effects these microglia. We developed study human brains test hypothesis involved progression. speculated if unique neuropathological change, they would substantially more common change than neurodegenerative diseases proteinopathies, e.g. α-synuclein or transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology. Our analyses used histologically stained sections from five brain regions 64 individuals across six states, healthy controls advanced stages, including comparative conditions such as Lewy body limbic-predominant age-related TDP-43 encephalopathy change. Using stereological sampling digital pathology, we assessed populations ramified, hypertrophic found significant increase areas affected early suggesting disease-specific neuropathology. Mediation analysis structural equation modelling impact regional spread In mediation model, was initiating factor leading development which then tau. These results loss protective could contribute further research preserving microglial function warranted.

Язык: Английский

Процитировано

8

NG-497 Alleviates Microglia-Mediated Neuroinflammation in a MTNR1A-Dependent Manner DOI
Qi Li, Pinyi Liu,

Xuan Zhu

и другие.

Inflammation, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Язык: Английский

Процитировано

1