Neuroinflammation in Alzheimer disease

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

Опубликована: Дек. 9, 2024

Язык: Английский

---

Redox regulation: mechanisms, biology and therapeutic targets in diseases

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

---

Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications

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

---

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

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

---

Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress

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

Опубликована: Авг. 26, 2024

Язык: Английский

---

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4

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

---

Exploring the link between dystrophic microglia and the spread of Alzheimer's neuropathology

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

---

NG-497 Alleviates Microglia-Mediated Neuroinflammation in a MTNR1A-Dependent Manner

Inflammation, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Язык: Английский

---

The circular RNA circbabo(5,6,7,8S) regulates lipid metabolism and neuronal integrity via TGF-β/ROS/JNK/SREBP signaling axis in Drosophila

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

---

Do microglia metabolize fructose in Alzheimer’s disease?

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

Опубликована: Март 15, 2025

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder with a complex etiology. While emerging AD therapeutics can slow cognitive decline, they may worsen dementia in certain groups of individuals. Therefore, alternative treatments are much needed. Microglia, the brain resident macrophages, have potential to be novel therapeutic targets as regulate many facets AD, including lipid droplet (LD) accumulation, amyloid beta (Aβ) clearance, and neuroinflammation. To carry out such functions, microglia undergo phenotypic changes, which linked shifts metabolism substrate utilization. homeostatic driven by oxidative phosphorylation (OXPHOS) glycolysis, aging shift further towards glycolysis. Interestingly, this "metabolic reprogramming" increase fructose metabolism. In brain, predominantly express transporter SLC2A5 (GLUT5), enzymes involved fructolysis endogenous production, their expression being upregulated disease. Here, we review evidence for uptake, breakdown, production microglia. We also evaluate literature targeting periphery assess its ability modulate microglial function AD. The transport utilize fructose, coupled well-established role metabolic dysfunction, supports notion that target

Язык: Английский

---