Inflammatory aspects of Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Aug. 28, 2024

Language: Английский

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Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy

Protein & Cell, Journal Year: 2024, Volume and Issue: unknown

Published: May 11, 2024

Abstract Alzheimer’s disease (AD), the leading cause of dementia, is characterized by accumulation amyloid plaques and neurofibrillary tangles in brain. This condition casts a significant shadow on global health due to its complex multifactorial nature. In addition genetic predispositions, development AD influenced myriad risk factors, including aging, systemic inflammation, chronic conditions, lifestyle, environmental exposures. Recent advancements understanding pathophysiology are paving way for enhanced diagnostic techniques, improved assessment, potentially effective prevention strategies. These discoveries crucial quest unravel complexities AD, offering beacon hope management treatment options millions affected this debilitating disease.

Language: Английский

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The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: June 1, 2024

Abstract Although apoptosis, pyroptosis, and ferroptosis have been implicated in AD, none fully explains the extensive neuronal loss observed AD brains. Recent evidence shows that necroptosis is abundant closely linked to appearance of Tau pathology, markers accumulate granulovacuolar neurodegeneration vesicles (GVD). We review here neuron-specific activation mediated neuronal-necroptosis pathway, potential AD-relevant triggers upstream this interaction necrosome with endo-lysosomal possibly providing links pathology. In addition, we underscore therapeutic inhibiting neurodegenerative diseases such as presents a novel avenue for drug development targeting preserve cognitive abilities. Such an approach seems particularly relevant when combined amyloid-lowering drugs.

Language: Английский

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Autophagy–lysosomal-associated neuronal death in neurodegenerative disease

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Sept. 11, 2024

Language: Английский

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Identification and validation of diagnostic biomarkers for temporal lobe epilepsy related to ferroptosis and potential therapeutic targets

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 10, 2025

Ferroptosis pathway activation is potentially correlated with temporal lobe epilepsy (TLE). However, the diagnostic significance and mechanism of ferroptosis-related genes (FRGs) in TLE require further investigation. A comprehensive analysis GSE134697 dataset from Gene Expression Omnibus (GEO) database using Weighted gene co-expression network (WGCNA) identified 3,212 differentially expressed (DEGs) between (TLE) control groups, a critical focus on turquoise module. Through intersection DEGs key module genes, correlation analyses functional-related (FRG), protein-protein interactions (PPI), least absolute shrinkage selection operator (LASSO), machine learning methods, five potential biomarkers ferroptosis (CBS, SHMT1, RIN3, QDPR, PLPP4) were isolated. nomogram was constructed these markers, enrichment revealed their links to T-cell activation, allograft rejection, glial differentiation. Variations 13 immune cell types also noted. Upregulation CBS, PLPP4 confirmed through RT-qPCR Western blot assays. Additionally, SHMT1-targeting one CBS-targeting drugs predicted Drug-Gene Interaction Database (DGIdb). These findings provide new insights into pathogenesis suggest targets for future research.

Language: Английский

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Alzheimer's disease neuropathology and its estimation with fluid and imaging biomarkers

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 14, 2025

Abstract Alzheimer’s disease (AD) is neuropathologically characterized by the extracellular deposition of amyloid-β peptide (Aβ) and intraneuronal accumulation abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied other co-pathologies in brain that may contribute to cognitive impairment, such as vascular lesions, transactive-response DNA-binding protein 43 (TDP-43), and/or α-synuclein (αSyn) aggregates. To estimate extent AD patients, several biomarkers have been developed. Specific tracers target visualize Aβ plaques, p-τ αSyn pathology or inflammation positron emission tomography. In addition imaging biomarkers, cerebrospinal fluid, blood-based biomarker assays reflecting AD-specific non-specific processes either already clinical use development. this review, we will introduce pathological brain, related discuss what respective determined at post-mortem histopathological analysis. It became evident initial stages plaque not detected with currently available biomarkers. Interestingly, precedes deposition, especially beginning when unable detect it. Later, takes lead accelerates pathology, fitting well known evolution measures over time. Some still lack clinically established today, TDP-43 cortical microinfarcts. summary, specific for AD-related pathologies allow accurate diagnosis based on pathobiological parameters. Although current excellent pathologies, they fail which analysis required. Accordingly, neuropathological studies remain essential understand development early stages. Moreover, there an urgent need co-pathologies, limbic predominant, age-related encephalopathy-related modify interacting p-τ. Novel approaches vesicle-based cryptic RNA/peptides help better future.

Language: Английский

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Spotlight on necroptosis: Role in pathogenesis and therapeutic potential of intervertebral disc degeneration

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 138, P. 112616 - 112616

Published: July 2, 2024

Language: Английский

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Neuronal regulated cell death in aging-related neurodegenerative diseases: key pathways and therapeutic potentials

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(8), P. 2245 - 2263

Published: July 29, 2024

Regulated cell death (such as apoptosis, necroptosis, pyroptosis, autophagy, cuproptosis, ferroptosis, disulfidptosis) involves complex signaling pathways and molecular effectors, has been proven to be an important regulatory mechanism for regulating neuronal aging death. However, excessive activation of regulated may lead the progression aging-related diseases. This review summarizes recent advances in understanding seven forms age-related Notably, newly identified ferroptosis cuproptosis have implicated risk cognitive impairment neurodegenerative These exacerbate disease by promoting inflammation, oxidative stress, pathological protein aggregation. The also provides overview key crosstalk mechanisms among these forms, with a focus on disulfidptosis. For instance, FDX1 directly induces copper ion valency dihydrolipoamide S-acetyltransferase aggregation, while mediates glutathione peroxidase 4 degradation, enhancing sensitivity. Additionally, inhibiting Xc- transport system prevent can increase disulfide formation shift NADP + /NADPH ratio, transitioning insights help uncover potential connections novel differentiate them from traditional mechanisms. In conclusion, identifying targets their points various aid developing specific biomarkers reverse clock treat conditions.

Language: Английский

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Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(771)

Published: Oct. 30, 2024

Necroptosis is a regulated form of cell death that has been observed in Alzheimer’s disease (AD) along with the classical pathological hallmark lesions amyloid plaques and Tau neurofibrillary tangles. To understand neurodegenerative process AD, we studied role necroptosis mouse models primary neurons. Using immunohistochemistry, demonstrated activated necroptosis-related proteins transgenic mice developing pathology neurons from precursor protein (APP)–Tau double treated phosphorylated seeds derived patient AD but not APP only exhibited β-amyloid deposits. granulovacuolar degeneration (GVD) bodies were associated neuronal loss brain regions also known to be vulnerable GVD human brain. inhibitors lowered percentage showing reduced loss, both This suggests GVD-associated refer as “GVD-necroptosis” may represent delayed AD. We propose inhibition could rescue this type

Language: Английский

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Physical Exercise Decreases Complement‐Mediated Synaptic Loss and Protects Against Cognitive Impairment by Inhibiting Microglial Tmem9‐ATP6V0D1 in Alzheimer's Disease

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

ABSTRACT Physical exercise is known to slow synaptic neurodegeneration and cognitive aging in Alzheimer's disease (AD). The benefits of physical are related reduced amyloid beta (A β ) deposition increased plasticity. Yet little about the mechanisms that mediate these effects. Here, we show down‐regulated microglial Tmem9 protein, inhibited C1q activation, decreased C1q‐dependent synapse engulfment, eventually ameliorating impairment 5xFAD mice. Furthermore, using oA cultured‐BV2 vitro, downregulation was sufficient restrain complement activity decrease microglia‐mediated loss, whereas overexpression tended promote activation induced abolishing exercise‐associated protection. Finally, contributed by regulating ATP6V0D1, a vesicular (H + ATP‐dependent proton pump (V‐ATPase) subunit regulates V‐ATPase assembly. Together, our results demonstrate potential treatment for AD patients. In an mouse model, it levels inhibit complement, alleviated complement‐dependent ameliorated emotional disorders.

Language: Английский

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