Seeing is Believing: Facile Amphiphilic AIEgen Unveils Selective and Ultrafast Wash-Free Dead Cell Imaging

Sensors and Actuators B Chemical, Journal Year: 2025, Volume and Issue: unknown, P. 137383 - 137383

Published: Feb. 1, 2025

Language: Английский

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Advances in the Study of Necroptosis in Vascular Dementia: Focus on Blood–Brain Barrier and Neuroinflammation

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(2)

Published: Feb. 1, 2025

ABSTRACT Background Vascular dementia (VaD) includes a group of brain disorders that are characterized by cerebrovascular pathology.Neuroinflammation, disruption the blood–brain barrier (BBB) permeability, white matter lesions, and neuronal loss all significant pathological manifestations VaD play key role in disease progression. Necroptosis, also known asprogrammed necrosis, is mode programmed cell death distinct from apoptosis closely associated with ischemic injury neurodegenerative diseases. Recent studies have shown necroptosis exacerbates BBB destruction, activates neuroinflammation, promotes loss, severely affects prognosis. Results Conclusions In this review, we outline roles its molecular mechanisms process VaD, particular focus on modulating neuroinflammation exacerbating permeability elaborate regulatory centrally involved cells mediated tumor necrosis factor‐α VaD. We analyze possibility specific strategy targeting would help inhibit destruction With necroptosis, study delved into impact changes prognosis to provide new treatment ideas.

Language: Английский

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Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer’s disease

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 15, 2025

Abstract Pathological tau isoforms, including hyperphosphorylated at serine 396 (pS396-tau) and oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) AD dementia. These exhibit significant retinal ganglion cell (RGC) loss, however presence isoforms RGCs their impact on RGC integrity, particularly early AD, have not been studied. Here, we analyzed superior temporal cross-sections from 25 MCI or 16 age- sex-matched cognitively normal controls. Using marker ribonucleic acid binding protein multiple splicing (RBPMS) Nissl staining, found a 46–56% reduction RBPMS + neurons layer (GCL) ( P < 0.05–0.001). loss was accompanied by soma hypertrophy (10–50% enlargement, 0.05–0.0001), nuclear displacement, apoptosis (30–50% increase, 0.05–0.01), prominent expression granulovacuolar degeneration (GVD) bodies GVD-necroptotic markers. Both pS396-tau Oligo-tau were identified RGCs, hypertrophic cells. PS396-tau counts significantly increased 2.1–3.5-fold versus control 0.05–0.0001). Tauopathy-laden strongly inter-correlated r =0.85, 0.0001) tauopathy associated =-0.40–(-0.64), 0.05–0.01). Their abundance correlated brain pathology deficits, higher tauopathy-laden Braak stages (V–VI), clinical dementia ratings (CDR = 3), mini-mental state examination (MMSE ≤ 26) scores. central mid-periphery showed closest associations status, while exhibited strongest correlations (NFTs, stages, ABC scores; S =0.78–0.81, 0.001–0.0001) decline (MMSE; =-0.79, 0.0019). Overall, these findings identify link between pathogenic involving apoptotic death pathways. Future research should validate results larger more diverse cohorts develop as potential noninvasive biomarker for detection monitoring progression.

Language: Английский

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Role of tau versus TDP‐43 pathology on medial temporal lobe atrophy in aging and Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(2)

Published: Feb. 1, 2025

Abstract Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal was thought to result from tau tangles AD, different neuropathologies can lead atrophy, especially TAR DNA‐binding protein 43 (TDP‐43) pathology. In this narrative review, we evaluate existing studies the relative contribution of and TDP‐43 pathology medial temporal lobe (MTL) atrophy. We report a clear association both neuropathology with MTL even after correcting for other neuropathologies. Next, discuss potential synergism between timing effects Finally, avenues future research will be discussed. A better understanding interplay their effect help development more specific biomarkers limbic‐predominant age‐related encephalopathy pinpointing optimal testing anti‐tau anti‐TDP‐43 treatments trials. Highlights Both contribute There positive potentially synergism. It unclear if have additive or synergistic The remains unclear. Clarifying improve biomarkers.

Language: Английский

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Semaglutide Ameliorates Neuroinflammation Caused by Enterogenous Pyrogen in APP/PS1 Mice

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Background and purpose: Alzheimer's disease (AD) is a neurodegenerative characterized by progressive cognitive dysfunction, which common in the elderly. In recent years, it has been reported that glucagon-like peptide 1 (GLP-1) analogues have neuroprotective function. However, mechanism of GLP-1 improving neurological function not fully clarified. This study attempts to clarify alleviating AD phenotype. Methods: this study, modified once-weekly analogue, Semaglutide, was used treat 8-month-old amyloid precursor protein / presenilin (APP/PS1) transgenic mice. By means ethology, molecular biology 16s rRNA amplicon sequencing, confirmed Semaglutide alleviated phenotype APP/PS1 Results: improved behavioral performance mice, reduced neuronal damage aggregation amyloid-β (Aβ) plaques, enhanced synaptic plasticity. also attenuated pyroptosis mediated NOD-like receptor thermal domain associated 3 (NLRP3), inflammatory reaction toll-like 4 (TLR4) mitochondrial microglia as well structure blood-brain barrier (BBB) Conclusion: may repair alleviate central nervous system injury caused displacement pyrogen gut

Language: Английский

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Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator

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

Published: June 1, 2024

Abstract Alzheimer’s disease (AD) is the most common cause of dementia, and mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying familial AD APP V717I mutation after injection into mouse forebrain. mutant iPSCs isogenic controls were differentiated revealing enhanced Aβ 42 production, elevated phospho-tau, impaired neurite outgrowth neurons. Two months transplantation, control neural cells showed robust engraftment but at 12 post-injection, grafts smaller demonstrated compared to controls, while plaque tangle pathology seen. Single-nucleus RNA-sequencing micro-dissected grafts, performed 2 injection, identified significantly altered transcriptome signatures iPSC-derived pointing towards dysregulated synaptic function axon guidance. Interestingly, an increased expression genes, many which also upregulated postmortem patients including transmembrane protein LINGO2. Downregulation LINGO2 cultured rescued deficits reversed key AD-associated transcriptional related limited function, apoptosis cellular senescence. These results provide important insights dysregulation xenografted linked they indicate that may represent a potential therapeutic target AD.

Language: Английский

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Identification of early Alzheimer’s disease subclass and signature genes based on PANoptosis genes

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 22, 2024

Introduction Alzheimer’s disease (AD) is one of the most prevalent forms dementia globally and remains an incurable condition that often leads to death. PANoptosis represents emerging paradigm in programmed cell death, integrating three critical processes: pyroptosis, apoptosis, necroptosis. Studies have shown necroptosis, pyroptosis play important roles AD development. Therefore, targeting genes might lead novel therapeutic targets clinically relevant approaches. This study aims identify different molecular subtypes potential drugs for treating based on PANoptosis. Methods Differentially expressed associated with were identified via Gene Expression Omnibus (GEO) dataset GSE48350, GSE5281, GSE122063. Least Absolute Shrinkage Selection Operator (LASSO) regression was employed construct a risk model linked these genes. Consensus clustering analysis conducted define We further performed gene set variation (GSVA), functional enrichment analysis, immune infiltration investigate differences between subtypes. Additionally, protein-protein interaction (PPI) network established hub genes, DGIdb database consulted compounds Single-cell RNA sequencing utilized assess expression at cellular level across Results A total 24 differentially (APANRGs) AD, leading classification two distinct subgroups. The results indicate subgroups exhibit varying progression states, early subtype primarily dysfunctional synaptic signaling. Furthermore, we from (DEGs) clusters predicted 38 candidate treatment revealed key are predominantly neuronal cells, while differential metabolic found endothelial cells astrocytes. Conclusion In summary, subtypes, including abnormality as well immune-metabolic subtype. ten SLC17A7, SNAP25, GAD1, SLC17A6, SLC32A1, PVALB, SYP, GRIN2A, SLC12A5, SYN2, marker These findings may provide valuable insights diagnosis contribute development innovative strategies.

Language: Английский

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Amygdala-predominant α-synuclein pathology is associated with exacerbated hippocampal neuron loss in Alzheimer’s disease

Brain Communications, Journal Year: 2024, Volume and Issue: 6(6)

Published: Jan. 1, 2024

Misfolded α-synuclein protein accumulates in 43-63% of individuals with symptomatic Alzheimer's disease. Two main patterns comorbid pathology have been identified: caudo-rostral and amygdala-predominant. α-Synuclein aggregates shown to interact the transactive response DNA-binding 43 (TDP-43) abnormally phosphorylated tau protein. All these proteins accumulate amygdala, which is anatomically connected hippocampus. However, specific role amygdala-predominant progression disease hippocampal degeneration remains unclear. In this cross-sectional study, we analysed 291 autopsy brains from both demented non-demented elderly neuropathologically. Neuronal density CA1 region hippocampus was assessed for all cases. We semiquantitatively evaluated severity across seven brain regions calculated a ratio limbic brainstem severity, used stratify cases into two distinct spreading patterns. 99 cases, limbic-predominant age-related TDP-43 neuropathological changes density. performed triple fluorescence staining medial temporal lobe samples antibodies against TDP-43, tau. Finally, employed path analysis determine association network various parameters neuronal identified an between αSyn pattern decreased region. found that exhibited highest prevalence inclusions dentate gyrus among groups, while those had lowest changes. observed colocalization aggregated hyperphosphorylated cytoplasmic within amygdala neurons Path modelling suggests relationship neuron loss partially mediated by aggregates. Our findings suggest may constitute group more severe damage, higher burden potential interactions α-synuclein,

Language: Английский

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Functional Relationships between L1CAM, LC3, ATG12, and Aβ

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10829 - 10829

Published: Oct. 9, 2024

Abnormal protein accumulations in the brain are linked to aging and pathogenesis of dementia various types, including Alzheimer’s disease. These can be reduced by cell indigenous mechanisms. Among these is autophagy, whereby proteins transferred lysosomes for degradation. Autophagic dysfunction hampers elimination pathogenic aggregations that contribute death. We had observed adhesion molecule L1 interacts with microtubule-associated 1 light-chain 3 (LC3), which needed autophagy substrate selection. increases survival an LC3-dependent manner via its extracellular LC3 interacting region (LIR). also Aβ reduces plaque load AD model mouse. Based on results, we investigated whether could aggregated clearance. here show autophagy-related 12 (ATG12) LIR domain, whereas interaction ubiquitin-binding p62/SQSTM1 does not depend LIR. Aβ, bound L1, carried autophagosome leading elimination. Showing mitophagy-related L1-70 fragment ubiquitinated, expect pathway contributes propose enhancing functions may therapy humans.

Language: Английский

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Regulated cell death in neurodegeneration: pathways and therapeutic horizons

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

Published: Sept. 24, 2024

Language: Английский

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