The Challenges of Modulating Neuroinflammation in Alzheimer's Disease and Multiple Sclerosis with TREM2 Agonistic Antibodies DOI

Juliette R. Houchois,

Jonathan E. Attwood

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 44(50), P. e1869242024 - e1869242024

Published: Dec. 11, 2024

Alzheimer's disease (AD) and multiple sclerosis (MS) are neurodegenerative diseases in which aberrant inflammatory processes thought to contribute progressive disability. Although MS is characterized by demyelinated lesions AD amyloid-β plaques neurofibrillary tangles, both involve the activation of resident macrophages known as microglia. Microglia act central mediators neuroinflammation through a variety mechanisms including release immunomodulatory cytokines phagocytosis toxic debris, such damaged myelin (Sen et al., 2022; Zhang 2023). Acute can protect nervous system; however, dysregulation this response lead chronic damaging effects. Consequently, microglia have emerged promising therapeutic targets for these diseases. The triggering receptor expressed myeloid cells 2 (TREM2) transmembrane protein that key regulator (Ulland Colonna, 2018; TREM2 recognizes damage-associated lipids instructs respond pathological insults proliferating, initiating phagocytosis, increasing energy metabolism (Schlepckow 2023; Previous studies using animal models shown required transition from resting surveillance state into disease-associated (DAM), actively engage with core features pathology. In models, enables DAM form protective barriers around demyelination used study MS, influences recruitment sites, clearance remyelination (Cignarella 2020). Activated eventually cleaved, attenuating releasing soluble (sTREM2). role sTREM2 unclear. It was initially considered passive biomarker pathology; more recent overexpression associated beneficial … Correspondence should be addressed Juliette R. Houchois at juliette.houchois{at}medschool.ox.ac.uk.

Language: Английский

Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer’s Disease Therapeutics DOI Creative Commons
Daniela Dias, Renato Socodato

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 279 - 279

Published: Jan. 23, 2025

Alzheimer’s disease (AD) is traditionally viewed through the lens of amyloid cascade hypothesis, implicating amyloid-beta and tau protein aggregates as main pathological culprits. However, burgeoning research points to brain’s resident immune cells, microglia, critical players in AD pathogenesis, progression, potential therapeutic interventions. This review examines dynamic roles microglia within intricate framework AD. We detail involvement these cells neuroinflammation, explaining how their activation response fluctuations may influence trajectory. further elucidate complex relationship between pathology. study highlights dual nature which contribute both aggregation clearance protein. Moreover, an in-depth analysis interplay unveils significant, yet often overlooked, impact this interaction on neurodegeneration Shifting from conventional approaches, we assess current treatments primarily targeting introduce novel strategies that involve manipulating microglial functions. These innovative methods herald a paradigm shift management Finally, explore field precision diagnosis pursuit robust biomarkers. underline more profound comprehension biology could enrich essential areas, potentially paving way for accurate diagnostic tools tailored treatment strategies. In conclusion, expands perspective pathology treatment, drawing attention multifaceted microglia. As continue enhance our understanding microglial-focused interventions emerge promising frontier bolster arsenal fight against

Language: Английский

Citations

4
Neuroinflammatory Biomarkers in Alzheimer’s Disease: From Pathophysiology to Clinical Implications DOI Open Access
Fausto Roveta, Lucrezia Bonino, Elisa Maria Piella

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 11941 - 11941

Published: Nov. 6, 2024

The identification of neuroinflammation as a critical factor in Alzheimer's disease (AD) has expanded the focus research beyond amyloid-β and tau pathology. neuroinflammatory fluid biomarkers GFAP, sTREM2, YKL-40 have gained attention for their potential early detection monitoring progression. Plasma GFAP demonstrated promise predicting conversion from mild cognitive impairment to AD dementia, while sTREM2 highlights microglial activation, although there are conflicting results regarding its dynamics pathogenesis. Advanced imaging techniques, such PET tracers targeting TSPO MAO-B, also been developed visualize glial activation vivo, offering spatial temporal insights into processes. However, clinical implementation these faces challenges due lack specificity, many them can be elevated other conditions. Therapeutic strategies emerging, with TREM2-targeting therapies antidiabetic drugs like GLP-1 receptor agonists showing modulating activity. Nevertheless, complexity neuroinflammation, which encompasses both protective harmful responses, necessitates further fully unravel role optimize therapeutic approaches AD.

Language: Английский

Citations

6
Unraveling the inflammation–degeneration tangle in early MS: preliminary insights from ferritin, neurogranin, TREM2, and retinal ganglion cell layer DOI Creative Commons
Aurora Zanghì, A Greco, Ermete Giancipoli

et al.

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(2)

Published: Jan. 15, 2025

Multiple sclerosis (MS) involves a complex interplay between immune-mediated inflammation and neurodegeneration. Recent advances in biomarker research have provided new insights into the molecular underpinnings of MS, including ferritin, neurogranin, Triggering Receptor Expressed on Myeloid cells 2 (TREM2), neurofilaments light chain. This pilot study aims to investigate levels these biomarkers cerebrospinal fluid (CSF) MS patients explore their associations with clinical, cognitive, optical coherence tomography (OCT) parameters. cross-sectional included 26 relapsing (RMS) 13 symptomatic controls (SCs). Clinical, OCT assessments were performed, CSF samples analyzed for TREM2, neurofilaments. Neurogranin significantly higher RMS compared SCs (p = 0.04), receiver-operating characteristic (ROC) analysis indicated that neurogranin could be considered disease (AUC 0.733, p 0.01). Ferritin showed strong positive correlation (r 0.690, < 0.01), both inversely correlated retinal ganglion cell layer (GCL) thickness. TREM2 was positively associated baseline Expanded Disability Status Scale score. suggests may potential at time diagnosis, highlights relationship inflammation, oxidative stress, neuronal damage MS. The inverse association ferritin GCL thickness warrants further investigation role iron metabolism synaptic early stages disease.

Language: Английский

Citations

0
Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination DOI Creative Commons
Jinchao Hou, Roberta Magliozzi, Yun Chen

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(13)

Published: March 25, 2025

We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration brain. TREM2 is a receptor that activates microglia, which are crucial for clearing debris and promoting remyelination. Previous studies mouse model demyelination induced by copper-chelating agent Cuprizone (CPZ) have shown stimulation with monoclonal antibody reduces demyelination, while deleting Trem2 gene mice impairs Here, we blocked function acutely an during both remyelination phases CPZ analyzed impact treatment myelination expression single cells. found blocking depleted distinct population microglia high transcription factor MAFB The loss these MAFB-high was linked to impaired generation myelinating oligodendrocytes. Importantly, identified + acute acute-chronic brain lesions from individuals multiple sclerosis (MS), but not inactive lesions. conclude essential maintaining associated repair. This finding has significant implications understanding demyelinating diseases like MS suggests stimulating could be promising therapeutic approach

Language: Английский

Citations

0
The dual role of microglia in Alzheimer’s disease: from immune regulation to pathological progression DOI Creative Commons
Cong He, Baojiang Chen,

Hecai Yang

et al.

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: March 27, 2025

Alzheimer’s disease (AD) is a widespread neurodegenerative disorder and one of the major challenges for public health. Despite extensive research, role microglia in AD remains complex dual. The aim this review to summarize most recent advances research regarding dual concerning both immunomodulation pathological progression by considering mechanisms activation microglia, effects on Aβ clearance, tau pathology, impacts due genetic variations microglial functions. Among these findings are status M1 M2 phenotypes, crucial that variants like TREM2 have modulating response microglia. This describes how modulation signaling pathway might be exploited therapeutically treatment underlines relevance personalized medicine approach.

Language: Английский

Citations

0
Compound muscle action potential as an early functional in vivo measure of Sarm1 inhibition after sciatic nerve transection DOI

Seong Kwon Hur,

Rebecca Leahey,

Mitchell Geringer

et al.

Journal of Neuropathology & Experimental Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: June 6, 2025

Abstract The NADase sterile alpha and TIR motif containing 1 (Sarm1) protein drives axon degeneration after injury. Loss or inhibition of Sarm1 structurally protects axons sciatic nerve transection (SNT) in vivo but whether also functional loss injury is less clear. We established compound muscle action potential (CMAP) as a novel correlate activation SNT mouse model evaluated its relationship with biochemical Cellpose-based histological detection measure. CMAP amplitudes were elicited 8 h post-SNT reached near-floor levels by 24 h. Decreases amplitude are delayed gene dose-dependent manner knockout mice pharmacological inhibition. Myelinated density, the NAD hydrolysis product cyclic adenosine diphosphate ribose (cADPR), plasma biomarker neurofilament light (NfL) all altered Sarm1-dependent manner. In wild type mice, density NfL at time points that cADPR loss, indicating deficits preceded structural deficits. conclude declines measures can serve novel, preclinical, functional, pharmacodynamic readout for

Language: Английский

Citations

0
CD33 Ameliorates Surgery-Induced Spatial Learning and Memory Impairments Through TREM2 DOI

Jie Zou,

Yaxuan Wang, Xinyue Zhang

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Language: Английский

Citations

2
Identification of conserved and tissue-restricted transcriptional profiles for lipid associated macrophages (LAMs) DOI Creative Commons
Yingzheng Xu, Hannah Hillman, Michael Chang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 26, 2024

Abstract Macrophages are essential immune cells present in all tissues, and vital for maintaining tissue homeostasis, surveillance, responses. Considerable efforts have identified shared tissue-specific gene programs macrophages across organs during homeostasis. This information has dramatically enhanced our understanding of tissue-restricted macrophage programming function. However, few studies addressed the overlapping responses subsets following inflammatory One subset that been observed several studies, lipid-associated (LAMs), gained interest due to their unique role lipid metabolism potential as a therapeutic target. LAMs associated with regulating disease outcomes metabolically related disorders including atherosclerosis, obesity, nonalcoholic fatty liver (NAFLD). In this study, we utilized single-cell RNA sequencing (scRNAseq) data profile multiple tissues sterile conditions mice humans. Integration from various models revealed share set conserved transcriptional profiles, Trem2 Lpl , but also key sets LAM programs. Importantly, markers were highly human populations emerge chronic settings. Overall, analysis provides detailed landscape offers insights into roles metabolic diseases. These may help instruct appropriate targets broad or interventions modulate disease.

Language: Английский

Citations

2
The Challenges of Modulating Neuroinflammation in Alzheimer's Disease and Multiple Sclerosis with TREM2 Agonistic Antibodies DOI

Juliette R. Houchois,

Jonathan E. Attwood

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 44(50), P. e1869242024 - e1869242024

Published: Dec. 11, 2024

Alzheimer's disease (AD) and multiple sclerosis (MS) are neurodegenerative diseases in which aberrant inflammatory processes thought to contribute progressive disability. Although MS is characterized by demyelinated lesions AD amyloid-β plaques neurofibrillary tangles, both involve the activation of resident macrophages known as microglia. Microglia act central mediators neuroinflammation through a variety mechanisms including release immunomodulatory cytokines phagocytosis toxic debris, such damaged myelin (Sen et al., 2022; Zhang 2023). Acute can protect nervous system; however, dysregulation this response lead chronic damaging effects. Consequently, microglia have emerged promising therapeutic targets for these diseases. The triggering receptor expressed myeloid cells 2 (TREM2) transmembrane protein that key regulator (Ulland Colonna, 2018; TREM2 recognizes damage-associated lipids instructs respond pathological insults proliferating, initiating phagocytosis, increasing energy metabolism (Schlepckow 2023; Previous studies using animal models shown required transition from resting surveillance state into disease-associated (DAM), actively engage with core features pathology. In models, enables DAM form protective barriers around demyelination used study MS, influences recruitment sites, clearance remyelination (Cignarella 2020). Activated eventually cleaved, attenuating releasing soluble (sTREM2). role sTREM2 unclear. It was initially considered passive biomarker pathology; more recent overexpression associated beneficial … Correspondence should be addressed Juliette R. Houchois at juliette.houchois{at}medschool.ox.ac.uk.

Language: Английский

Citations

0