tRF-AspGTC promotes intracranial aneurysm formation by controlling TRIM29-mediated galectin-3 ubiquitination DOI Creative Commons
Chao Wang, Bing Yu, Han Zhou

et al.

Research, Journal Year: 2024, Volume and Issue: 8

Published: Dec. 18, 2024

Transfer RNA-derived small RNAs, a recently identified class of noncoding play crucial role in regulating gene expression and are implicated cerebrovascular diseases. However, the specific biological roles mechanisms transfer RNAs intracranial aneurysms (IAs) remain unclear. In this study, we that RNA-Asp-GTC derived fragment (tRF-AspGTC) is highly expressed IA tissues both humans mice. tRF-AspGTC promotes formation by facilitating phenotypic switching vascular smooth muscle cells, increasing matrix metalloproteinase 9 expression, inducing oxidative stress inflammatory responses. Mechanistically, binds to galectin-3, inhibiting tripartite motif 29-mediated ubiquitination stabilizing galectin-3. This stabilization activates toll-like receptor 4/MyD88/nuclear factor kappa B pathway, further driving inflammation. Clinically, circulating exosomal demonstrates strong diagnostic efficacy for IAs as an independent risk occurrence. These findings highlight potential promising biomarker therapeutic target IAs.

Language: Английский

Microglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases DOI Creative Commons

Nima Javanmehr,

Kiarash Saleki,

Parsa Alijanizadeh

et al.

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: Nov. 17, 2022

Abstract Microglia represent the first line of immune feedback in brain. Beyond surveillance, they are essential for maintaining brain homeostasis. Recent research has revealed microglial cells' spatiotemporal heterogeneity based on their local and time-based functions trauma or disease when homeostasis is disrupted. Distinct "microglial signatures" have been recorded physiological states injuries, with discrete sometimes overlapping pro- anti-inflammatory functions. involved neurological repair processes, such as neurovascular unit restoration synaptic plasticity, manage extent damage due to phenotype switching. The versatility cellular phenotypes beyond classical M1/M2 classification, well double-edge actions microglia neurodegeneration, indicate need further exploration cell dynamics contribution neurodegenerative processes. This review discusses homeostatic different subsets focusing neuropathological conditions. Also, we address feasibility targeting a therapeutic strategy diseases.

Language: Английский

Citations

61
Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes DOI Creative Commons
Dong Won Kim, Kevin J. Tu,

Alice Wei

et al.

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Dec. 17, 2022

Amongst risk alleles associated with late-onset Alzheimer's disease (AD), those that converged on the regulation of microglia activity have emerged as central to progression. Yet, how canonical amyloid-β (Aβ) and tau pathologies regulate subtypes during progression AD remains poorly understood.We use single-cell RNA-sequencing profile from mice exhibiting both Aβ across We identify novel are induced in response a disease-stage-specific manner. To validate observation mouse models, we also generated snRNA-Seq dataset human superior frontal gyrus (SFG) entorhinal cortex (ERC) at different Braak stages.We show early-stage disease, interferon signaling induces subtype termed Early-stage AD-Associated Microglia (EADAM) pathologies. During late-stage second Late-stage (LADAM) is detected. While similar observed other models neurodegenerative magnitude composition gene signatures found EADAM LADAM distinct, suggesting necessity elicit their emergence. Importantly, pattern EADAM- LADAM-associated expression brains, early (Braak II)- or late VI/V)- stage respectively. Furthermore, several Siglec genes selectively expressed either LADAM. Siglecg white-matter-associated LADAM, Siglec-10, orthologue Siglecg, progressively elevated an AD-stage-dependent manner but not shown non-AD tauopathy.Using scRNA-Seq bearing and/or pathologies, by combination stage-specific Our findings suggest required for induction In addition, revealed Siglecs biomarkers potential therapeutic targets.

Language: Английский

Citations

42
Alzheimer’s disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy? DOI Creative Commons

Daniela Melchiorri,

Sara Merlo, Benjamin Micallef

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 2, 2023

Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading dementia and death, characterized by two pathological hallmarks, extracellular deposits amyloid beta (Aβ) intraneuronal neurofibrillary tangles (NFTs) consisting altered hyperphosphorylated tau protein. Both have been widely studied pharmacologically targeted for many years, without significant results. In 2022, positive data on monoclonal antibodies targeting Aβ, donanemab lecanemab, followed 2023 FDA accelerated approval lecanemab publication final results phase III Clarity AD study, strengthened hypothesis causal role Aβ in pathogenesis AD. However, magnitude clinical effect elicited drugs limited, suggesting that additional mechanisms may contribute disease. Cumulative studies shown inflammation as one main contributors recognition specific neuroinflammation synergic with NFTs cascades. The present review provides an overview investigational are trials. Moreover, their action, positioning cascade events occur brain throughout potential benefit/limitation strategy discussed highlighted well. addition, latest patent requests inflammation-targeting therapeutics be developed will also discussed.

Language: Английский

Citations

29
Injured sensory neurons-derived galectin-3 contributes to neuropathic pain via programming microglia in the spinal dorsal horn DOI

Leyan Shan,

Kangtai Xu,

Luyao Ji

et al.

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 117, P. 80 - 99

Published: Jan. 6, 2024

Language: Английский

Citations

17
Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations DOI Creative Commons
Mika P. Cadiz,

Katelin A. Gibson,

Kennedi T. Todd

et al.

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(2)

Published: Jan. 16, 2024

Aducanumab, an anti-amyloid immunotherapy for Alzheimer’s disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect aducanumab treatment withdrawal on neuritic dystrophy, astrocytes, microglia in APP/PS1 amyloid mouse model. found that reductions dystrophy during acute were accompanied by microglial astrocytic activation, recruitment to plaques adoption aducanumab-specific pro-phagocytic pro-degradation transcriptomic signature, indicating a role aducanumab-mediated Aβ clearance. Reductions sustained 15 but 30 wk after discontinuation, reaccumulation coincided with loss signature failure reactivate. This suggests despite initial benefit from treatment, unable respond later restrain reaccumulation, making further studies amyloid-directed crucial assessing safety efficacy.

Language: Английский

Citations

14
PRKAA2, MTOR, and TFEB in the regulation of lysosomal damage response and autophagy DOI
Mohd Shariq, Mohammad Firoz Khan, Reshmi Raj

et al.

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(3), P. 287 - 311

Published: Jan. 6, 2024

Language: Английский

Citations

12
A molecular brain atlas reveals cellular shifts during the repair phase of stroke DOI Creative Commons
R. Weber, Beatriz Achón Buil, Nora H. Rentsch

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: April 18, 2025

Ischemic stroke triggers a cascade of pathological events that affect multiple cell types and often lead to incomplete functional recovery. Despite advances in single-cell technologies, the molecular cellular responses contribute long-term post-stroke impairment remain poorly understood. To gain better insight into underlying mechanisms, we generated transcriptomic atlas from distinct brain regions using mouse model permanent focal ischemia at one month post-injury. Our findings reveal cell- region-specific changes within stroke-injured peri-infarct tissue. For instance, GABAergic glutamatergic neurons exhibited upregulated genes signaling pathways involved axon guidance synaptic plasticity, downregulated associated with aerobic metabolism. Using cell-cell communication analysis, identified increased strength predicted interactions tissue among both neural non-neural cells via such as those involving collagen, protein tyrosine phosphatase receptor, neuronal growth regulator, laminin, several adhesion molecules. Furthermore, found strong correlation between transcriptome after observed human nonfatal lesions. Common features were linked inflammatory responses, extracellular matrix organization, angiogenesis. provide detailed resource for advancing our understanding pathology discovering therapeutic targets repair phase

Language: Английский

Citations

2
Macrophages protect against sensory axon loss in peripheral neuropathy DOI Creative Commons
Sara Hakim, Aakanksha Jain, Stuart Adamson

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Language: Английский

Citations

1
Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease DOI Creative Commons
Juan García‐Revilla, Antonio Boza‐Serrano,

Yiyun Jin

et al.

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 146(1), P. 51 - 75

Published: May 18, 2023

Abstract Parkinson’s Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) known to be main component LB. It has also been reported interact with several proteins organelles. Galectin-3 (GAL3) have detrimental function diseases. galactose-binding protein without catalytic activity expressed mainly activated microglial cells central nervous system (CNS). GAL3 previously found outer layer LB post-mortem brains. However, role PD yet elucidated. In samples, we identified an association between all subjects studied. was linked less αSYN other deposits, including pale bodies. associated disrupted lysosomes. vitro studies demonstrate that exogenous recombinant Gal3 internalised neuronal cell lines primary where it interacts endogenous αSyn fibrils. addition, aggregation experiments show affects spatial propagation stability pre-formed fibrils resulting short, amorphous toxic strains. To further investigate these observations vivo, take advantage WT Gal3KO mice subjected intranigral injection adenovirus overexpressing human as model. line our , under conditions, genetic deletion leads increased intracellular accumulation within remarkably preserved integrity motor function. Overall, data suggest prominent for process formation, leading production short species detriment larger strains which triggers mouse model PD.

Language: Английский

Citations

18
Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice DOI
Tuancheng Feng, Huan Du,

Cha Yang

et al.

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

Published: March 25, 2024

Language: Английский

Citations

9