Cranial bone maneuver ameliorates Alzheimer's disease pathology via enhancing meningeal lymphatic drainage function

Alzheimer s & Dementia, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Abstract INTRODUCTION Alzheimer's disease (AD) is a progressive neurodegenerative and the leading cause of dementia. Recent research highlights meningeal lymphatics as key regulators in neurological diseases, suggesting that enhancing their drainage function could be potential therapeutic strategy for AD. Our proof‐of‐concept study demonstrated cranial bone transport can improve lymphatic promote ischemic stroke recovery. METHODS This defined maneuver (CBM) technique. After osteotomy, small circular flap was made attached to an external fixator subsequent controlled fashion period using 5xFAD mice. RESULTS CBM treatment improved memory functions, reduced amyloid deposits, promoted function. induced cascades inflammatory lymphangiogenic processes skull meninges. Meningeal are indispensable elements effects CBM. DISCUSSION might promising innovative therapy AD management, warranting further clinical investigation. Highlights Cranial alleviated deficits depositions. lymphangiogenesis The beneficial lasted long time following procedures. vessels effects.

Язык: Английский

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Meningeal Lymphatics in Central Nervous System Diseases

Annual Review of Neuroscience, Год журнала: 2024, Номер 47(1), С. 323 - 344

Опубликована: Апрель 22, 2024

Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous (CNS) fluid exchange, waste clearance, immune cell trafficking, and privilege. Meningeal lymphatics have also been demonstrated to functionally modify outcome neurological disorders their responses treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, neurodegenerative Alzheimer's Parkinson's diseases. In this review, we discuss evidence contribution diseases, well available experimental methods for manipulating in these conditions. Finally, provide a discussion pressing questions challenges utilizing prime target therapeutic intervention possibly drug delivery disorders.

Язык: Английский

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Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing

Neuron, Год журнала: 2025, Номер 113(5), С. 684 - 700.e8

Опубликована: Янв. 13, 2025

Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, we find that natural killer-like T (NKLT) cells seed intact human murine spinal multiply further after injury. NKLT accumulate in via C-X-C motif chemokine receptor 6 ligand 16 signaling to clonally expand by engaging with major histocompatibility complex (MHC)-I-expressing myeloid cells. expressing killer cell granule protein 7 (Nkg7) disrupt myeloid-cell-dependent wound healing injured cord. Nkg7 deletion mice curbs degranulation normalize phenotype, thus promoting repair axonal integrity. Monoclonal antibodies neutralizing CD8+ SCI enhance neurological recovery healing. Our results unveil a reversible role for NKG7+CD8+ exacerbating damage, suggesting clinically relevant treatment SCI.

Язык: Английский

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H4K12 Lactylation Activated‐Spp1 in Reprogrammed Microglia Improves Functional Recovery After Spinal Cord Injury

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(2)

Опубликована: Фев. 1, 2025

ABSTRACT Background Spinal cord injury (SCI) is a severe condition leading to significant disability and high mortality. The role of the secreted phosphoprotein 1 (SPP1) signaling pathway in SCI, which quickly activated after injury, critical for intercellular communication but remains poorly understood. Aims This study aimed explore function regulatory mechanisms SPP1 SCI investigate its potential as therapeutic target improving functional recovery injury. Materials Methods Single‐cell RNA sequencing (scRNA‐seq) was employed identify ligands receptors pathway, particularly microglia/macrophages. Recombinant (rSPP1) used vitro vivo assess effects on neuronal maturation, mitochondrial energy axons, SCI. Pseudotime analysis conducted examine Spp1 microglial activation proliferation. DNA‐pulldown experiments were performed upstream proteins . Results primarily localized microglia with rSPP1 promoting maturation enhancing axons. Injection into injured spinal resulted improvement recovery. indicated that involved proliferation microglia. Histone H4 lysine 12 lactylation (H4K12la) found promote transcription reprogrammed postinjury. Discussion Our findings reveal novel mechanism involving activation, function, glycolytic reprogramming. new insight provides deeper understanding contribution response. Conclusion uncovers previously unreported offering

Язык: Английский

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Lactate promotes microglial scar formation and facilitates locomotor function recovery by enhancing histone H4 lysine 12 lactylation after spinal cord injury

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Авг. 3, 2024

Lactate-derived histone lactylation is involved in multiple pathological processes through transcriptional regulation. The role of lactate-derived the repair spinal cord injury (SCI) remains unclear. Here we report that overall lactate levels and are upregulated after SCI. Notably, H4K12la was significantly elevated microglia injured cord, whereas exogenous treatment further Functionally, promoted microglial proliferation, scar formation, axon regeneration, locomotor function recovery Mechanically, lactate-mediated elevation PD-1 transcription microglia, thereby facilitating SCI repair. Furthermore, a series rescue experiments confirmed inhibitor or microglia-specific AAV-sh-PD-1 reversed therapeutic effects following This study illustrates mechanism lactate/H4K12la/PD-1 signaling microglia-mediated tissue provides novel target for therapy.

Язык: Английский

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Bioactive Peptide Hydrogel Scaffold with High Fluidity, Thermosensitivity, and Neurotropism in 3D Spatial Structure for Promoted Repair of Spinal Cord Injury

Small, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 8, 2024

Spinal cord injury (SCI) has been considered a clinically challenging disease that is characterized by local disturbance of the microenvironment, which inhibits post-injury neural regeneration. The simulation microenvironment conducive to regeneration spinal beneficial for SCI repair. In this study, bioactive composite hydrogels are developed mimic regenerative enhanced fabricated (CRP) based on chitosan (CS), RADA

Язык: Английский

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Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 13, 2025

Spinal cord injury (SCI) triggers a complex inflammatory response that impedes neural repair and functional recovery. The modulation of macrophage phenotypes is thus considered promising therapeutic strategy to mitigate inflammation promote regeneration. We employed microarray single-cell RNA sequencing (scRNA-seq) investigate gene expression changes immune cell dynamics in mice following crush at 3 7 days post-injury (dpi). High-dimensional co-expression network analysis (hdWGCNA) slingshot trajectory were identify key modules differentiation pathways. Subsequently, immunofluorescence staining, flow cytometry, western blotting performed validate the identified effects amantadine on inflammation. To elucidate molecular mechanisms underlying transcriptional level, we followed by set enrichment (GSEA). results revealed pathways related phagocytosis activation are significantly involved post-injury, shedding light regulatory role macrophages SCI repair. further within injured spinal cord, conducted scRNA-Seq, identifying three distinct subtypes: border-associated (BAMs), (IMs), chemotaxis-inducing (CIMs). Trajectory suggested pathway from Il-1b+ IMs Mrc1+ BAMs, subsequently Arg1+ CIMs, indicating potential maturation process. Given importance these response, utilized docking hypothesize might modulate this Subsequent vitro vivo experiments demonstrated reduces facilitates transition BAMs likely through HIF-1α NF-κB This promotes regeneration enhances recovery SCI. Amantadine modulates SCI, early responses, function These findings highlight as treatment for provide foundation future translational research into its clinical applications.

Язык: Английский

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Trehalose enhances macrophage autophagy to promote myelin debris clearance after spinal cord injury

Cell & Bioscience, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 29, 2025

Abstract Background Myelin-laden foamy macrophages accumulate extensively in the lesion epicenter, exhibiting characteristics of autophagolysosomal dysfunction, which leads to prolonged inflammatory responses after spinal cord injury (SCI). Trehalose, known for its neuroprotective properties as an autophagy inducer, has yet be fully explored potential mitigate macrophage formation and exert therapeutic effects context SCI. Results We observed that trehalose significantly enhances phagocytosis clearance myelin a dose-dependent manner vitro. In vivo, administration markedly reduced debris accumulation, inhibited formation, suppressed responses, decreased fibrotic scarring, promoted axonal growth motor function recovery These beneficial may related overexpression transcription factor EB (TFEB), key regulator autophagy-lysosomal system, can rescue autophagic dysfunction inhibit responses. Additionally, on were abolished by chloroquine, inhibitor, suggesting trehalose’s candidate enhancing post-SCI. Conclusions Our findings underscore pivotal role modulating within macrophages, providing new perspectives treatment injury. Graphical abstract

Язык: Английский

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The “Inner–Outer” Molecules-Loaded Fiber-Hydrogel Scaffolds Coordinate Specific Immunity and Neural Differentiation for Repairing SCI

ACS Materials Letters, Год журнала: 2024, Номер 6(3), С. 822 - 836

Опубликована: Фев. 5, 2024

The treatment of spinal cord injury (SCI) remains unsatisfactory because the inflammatory microenvironment and limited potential for nerve regeneration. However, most treatments have focused on modulating nonspecific immunity ignored importance specific in SCI. In this study, an "Inner–Outer" Metformin (Met) anti-CD80 monoclonal antibody (CD80 mAb)-loaded fiber-hydrogel scaffold (P/G-Met-CD80 mAb) was constructed through microsol-electrospinning UV illumination methods. P/G-Met-CD80 mAb scaffolds exhibited good biocompatibility hydrophilicity, facilitating cell proliferation adhesion. addition, were capable releasing CD80 Met sequentially, exerting their protected functions at different stages post-SCI rats. released early stage significantly inhibited immune response by blocking T-cell costimulatory activation reducing IL-2 secretion, improving after Late stage-released recruited neural stem cells (NSCs) to area enhanced NSCs differentiation into neurons. with immunomodulatory neurogenic provide a new strategy repairing SCI clinic.

Язык: Английский

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Elevated phagocytic capacity directs innate spinal cord repair

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

Опубликована: Июнь 13, 2024

Immune cells elicit a continuum of transcriptional and functional states after spinal cord injury (SCI). In mammals, inefficient debris clearance chronic inflammation impede recovery overshadow pro-regenerative immune functions. We found that, unlike zebrafish SCI elicits transient activation efficient clearance, without causing inflammation. Single-cell transcriptomics inducible genetic ablation showed macrophages are highly phagocytic required for regeneration. Cross-species comparisons between mammalian identified

Язык: Английский

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