Inflammatory microglia correlate with impaired oligodendrocyte maturation in multiple sclerosis

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 14, 2025

Introduction Remyelination of demyelinated axons can occur as an endogenous repair mechanism in multiple sclerosis (MS), but its efficacy varies between both MS individuals and lesions. The molecular cellular mechanisms that drive remyelination remain poorly understood. Here, we studied the relation microglia activation activity MS. Methods We correlated regenerative (CD163 + ) inflammatory (iNOS with BCAS1 oligodendrocytes, subdivided into early-stage (<3 processes) late-stage (≥3 cells brain donors high or low remyelinating potential remyelinated lesions active ramified/amoeboid (non-foamy) foamy microglia. A cohort categorized efficiently (ERDs; n=25) (PRDs; n=17) was included, based on their proportion at autopsy. Results discussion hypothesized more CD163 oligodendrocytes non-foamy from ERDs iNOS fewer PRDs. For microglia, however, no differences were observed donor groups. In line our hypothesis, found INOS significantly increased PRDs compared to within lesions, detected comparison Although for did find vs Interestingly, a positive correlation identified presence oligodendrocytes. These findings suggest impaired maturation encountering may underlie deficits unsuccessful lesion

Язык: Английский

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Microglia and Astrocytes in Alzheimer’s Disease: Significance and Summary of Recent Advances

Aging and Disease, Год журнала: 2023, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2023

Alzheimer’s disease, one of the most common forms dementia, is characterized by a slow progression cognitive impairment and neuronal loss. Currently, approved treatments for AD are hindered various side effects limited efficacy. Despite considerable research, practical have not been developed. Increasing evidence shows that glial cells, especially microglia astrocytes, essential in initiation AD. During progression, activated resident increases ability resting astrocytes to transform into reactive promoting neurodegeneration. Extensive clinical molecular studies show involvement astrocyte-mediated neuroinflammation pathology, indicating may be potential therapeutic targets This review will summarize significant recent advances pathogenesis three parts. First, we typical pathological changes discuss terms function phenotypic changes. Second, describe astrocytes’ physiological role These roles include inflammatory response, “eat me” “don’t eat signals, Aβ seeding, propagation, clearance, synapse loss, synaptic pruning, remyelination, demyelination. Last, pharmacological non-pharmacological therapies targeting We conclude development Therefore, understanding new critical future trials. Moreover, pharmacological, with specific investigating damage repair, promising research direction regarding treatment prevention.

Язык: Английский

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Microglia and TREM2

Neuropharmacology, Год журнала: 2024, Номер 257, С. 110020 - 110020

Опубликована: Май 29, 2024

Язык: Английский

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TREM2 alleviates white matter injury after traumatic brain injury in mice might be mediated by regulation of DHCR24/LXR pathway in microglia

Clinical and Translational Medicine, Год журнала: 2024, Номер 14(4)

Опубликована: Апрель 1, 2024

White matter injury (WMI) is an important pathological process after traumatic brain (TBI). The correlation between white functions and the myeloid cells expressing triggering receptor-2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism crucial for early remyelination demyelinating diseases. However, potential roles of TREM2 expression in WMI TBI have not yet explored.

Язык: Английский

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TREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Апрель 17, 2025

Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune predominantly by microglia in the brain. Recent studies have established TREM2 as a central signaling hub neurodegeneration, where it triggers responses upon sensing pathological development and tissue damages. binds diverse ligands activates downstream pathways that regulate microglial phagocytosis, inflammatory responses, metabolic reprogramming. Interestingly, exists both its membrane-bound form soluble variant (sTREM2), latter generated through proteolytic shedding or alternative splicing can be detected cerebrospinal fluid plasma. Emerging clinical preclinical evidence underscores potential of sTREM2 diagnostic biomarkers therapeutic targets Alzheimer’s disease (AD). This review provides comprehensive overview molecular functions, regulatory mechanisms, implications AD. Furthermore, we explore their roles diagnostics therapeutics while suggesting key research directions for advancing TREM2/sTREM2-based strategies combating

Язык: Английский

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Identifying Biomarkers for Remyelination and Recovery in Multiple Sclerosis: A Measure of Progress

Biomedicines, Год журнала: 2025, Номер 13(2), С. 357 - 357

Опубликована: Фев. 4, 2025

Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery the prevention further damage. A key area focus remyelination process, where researchers are studying effects pharmacotherapy on myelin repair mechanisms. compounds being tested for their potential to foster in different clinical settings through application less or more complex techniques assess efficacy. Objective: To review current methods biomarkers track regeneration over time people with MS (PwMS), implications promyelinating drug testing. Methods: Narrative review, based a selection PubMed articles discussing measure vivo functional PwMS. Results: Non-invasive tools, such as structural Magnetic Resonance Imaging (MRI) Positron Emission Tomography (PET), implemented repair, while other like evoked potentials, MRI, digital markers allow assessment recovery. These methods, alone combination, been employed obtain precise various trials MS. Conclusions: Combining identify restoration could yield novel biomarkers, enhancing accuracy trial outcomes remyelinating therapies

Язык: Английский

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TREM2 deficiency impairs the energy metabolism of Schwann cells and exacerbates peripheral neurological deficits

Cell Death and Disease, Год журнала: 2024, Номер 15(3)

Опубликована: Март 7, 2024

Abstract Triggering receptor expressed on myeloid cells-2 (TREM2) has been implicated in susceptibility to neurodegenerative disease. Schwann cells (SCs), the predominant glial cell type peripheral nervous system (PNS), play a crucial role myelination, providing trophic support for neurons and nerve regeneration. However, function of TREM2 SCs not fully elucidated. Here, we found that is but PNS. deficiency leads disruption glycolytic flux oxidative metabolism SCs, impairing proliferation. The energy crisis caused by triggers mitochondrial damage autophagy activating AMPK PI3K-AKT-mTOR signaling. Combined metabolomic analysis demonstrated energic substrates metabolic pathways were significantly impaired TREM2-deficient SCs. Moreover, impairs axonal growth sciatic nerve, accompanied exacerbation neurological deficits suppression regeneration mouse model acute motor neuropathy. These results indicate critical regulator exerts neuroprotective effects

Язык: Английский

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Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(3)

Опубликована: Март 1, 2024

Abstract Background Accumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in pathogenesis treatment for AD. Aims We aimed to update regulatory targets differentiation maturation OLs, emphasized key role OLs occurrence Methods This review first concluded OL with AD pathogenesis, then advanced based on both clinic basic experiments. Later, we extensively discussed possible application current progress diagnosis this complex disease. Results Molecules involving OLs’ or maturation, including various transcriptional factors, cholesterol homeostasis regulators, microRNAs could participate Clinical data point towards impairment patients. Basic research further supports central regulation pathologies. Additionally, classic drugs, donepezil, edaravone, fluoxetine, clemastine demonstrate their potential remedying models, new therapeutics from perspective is constantly being developed. Conclusions believe that dysfunction one important Factors regulating might be biomarkers early agents stimulating warrant development anti‐AD drugs.

Язык: Английский

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Neutral or detrimental effects of TREM2 agonist antibodies in preclinical models of Alzheimer's Disease and Multiple Sclerosis

Journal of Neuroscience, Год журнала: 2024, Номер 44(29), С. e2347232024 - e2347232024

Опубликована: Июнь 3, 2024

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts modulate therapeutically. Here, we characterize the activities three agonist antibodies in multiple mixed-sex mouse models Alzheimer's disease (AD) pathology remyelination. Receptor activation downstream signaling are explored vitro, active dose ranges determined vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-β (Aβ) (PS2APP) or combined Aβ tau (TauPS2APP), chronic antibody treatment had limited impact microglia engagement with pathology, overall burden, neuronal damage. demyelinating injuries triggered acutely lysolecithin, unexpectedly disrupted injury resolution. Likewise, myelin recovery for experiencing demyelination cuprizone. We highlight timing frequency across models. These results introduce important considerations future TREM2-targeting approaches.

Язык: Английский

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Mechanisms underlying the beneficial effects of physical exercise on multiple sclerosis: focus on immune cells

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Сен. 29, 2023

Multiple sclerosis (MS) is a prevalent neuroimmunological illness that leads to neurological disability in young adults. Although the etiology of MS heterogeneous, it well established aberrant activity adaptive and innate immune cells plays crucial role its pathogenesis. Several cell abnormalities have been described animal models, including T lymphocytes, B dendritic cells, neutrophils, microglia/macrophages, astrocytes, among others. Physical exercise offers valuable alternative or adjunctive disease-modifying therapy for MS. A growing body evidence indicates may reduce autoimmune responses triggered by This partially accomplished restricting infiltration peripheral into central nervous system (CNS) parenchyma, curbing hyperactivation facilitating transition balance from pro-inflammatory an anti-inflammatory state. review provides succinct overview correlation between physical exercise, pathology, highlights potential benefits as strategy prevention treatment

Язык: Английский

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