ArticleJournal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology2019
Inhibition of Bruton's Tyrosine Kinase Modulates Microglial Phagocytosis: Therapeutic Implications for Alzheimer's Disease.
Article in Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 2 of them syntheses that pooled it.
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Who cites it
55 citing papers in PubMed, 2 syntheses or guidelines pooled it, 95 citations in OpenAlex.
- Cerebrospinal fluid inflammatory biomarkers for disease progression in Alzheimer's disease and multiple sclerosis: a systematic review.Frontiers in immunology · 2023Pooled it
- Modeling Immunity In Vitro: Slices, Chips, and Engineered Tissues.Annual review of biomedical engineering · 2021Pooled it
- Determination of a clinically effective evobrutinib dose: Exposure-response analyses of a phase II relapsing multiple sclerosis study.Clinical and translational science · 2022Trial
- Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.The Lancet. Neurology · 2021Trial
- Nanoparticle-enriched mass spectrometry enables comprehensive plasma proteomics and reveals novel candidates for mild cognitive impairment.Scientific reports · 2026Article
- BTK promotes neuroinflammation after intracerebral hemorrhage involving hub genes and alterations in microglial functions.Scientific reports · 2026Article
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Mechanistic Considerations Across Relapsing and Progressive Disease.Molecules (Basel, Switzerland) · 2026Review
- PLCG2 signaling and genetic resilience in Alzheimer's disease.Molecular neurodegeneration · 2026Review
- Neuroinflammation at the Crossroads of Neurodegeneration: The Roles of Microglia and Astrocytes in Parkinson's Disease, Alzheimer's Disease, and Multiple Sclerosis.Neurosciences (Riyadh, Saudi Arabia) · 2026Review
- Severe Central Nervous System Fungal Infection Following Tirabrutinib Administration in a Patient with Refractory Primary Central Nervous System Lymphoma: A Case Report.NMC case report journal · 2026Article
- Identification of Potential Nontoxic HumanACS omega · 2025Article
- Article
- Tolebrutinib Phase 2b Long-Term Extension Study: Two-Year Safety, MRI, and Clinical Efficacy Outcomes in Patients With Relapsing Multiple Sclerosis Patients.Neurology open access · 2025Article
- Chronic oral administration of ibrutinib prevents long-term memory deficits and reduces AD pathology and neuroinflammatory responses in a mouse model of AD.Molecular brain · 2025Article
- Beyond relapses: How BTK inhibitors are shaping the future of progressive MS treatment.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Bruton Tyrosine Kinase in Lesions of Multiple Sclerosis and 3 of Its Models.Neurology(R) neuroimmunology & neuroinflammation · 2025Article
- Bruton's Tyrosine Kinase: A Potential Novel Target for Neurological Disorders.Physiological research · 2025Review
- Evobrutinib mitigates neuroinflammation after ischemic stroke by targeting M1 microglial polarization via the TLR4/Myd88/NF-κB pathway.Molecular medicine (Cambridge, Mass.) · 2025Article
- Inhibition of Bruton's tyrosine kinase restricts neuroinflammation following intracerebral hemorrhage.Theranostics · 2025Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bruton's tyrosine kinase (BTK), a critical component of B cell receptor signaling, has recently been implicated in regulation of the peripheral innate immune response. However, the role of BTK in microglia, the resident innate immune cells of the central nervous system, and its involvement in the pathobiology of neurodegenerative disease has not been explored. Here we found that BTK is a key regulator of microglial phagocytosis. Using potent BTK inhibitors and small interfering RNA (siRNA) against BTK, we observed that blockade of BTK activity decreased activation of phospholipase gamma 2, a recently identified genetic risk factor in Alzheimer's disease (AD), and reduced phagocytosis in rodent microglia and human monocyte-derived macrophages. Inhibition of BTK signaling also decreased microglial uptake of synaptosomes but did not have major impacts on other key microglial functions such as migration and cytokine release. Similarly, blocking BTK function ex vivo in acute brain slices reduced microglial phagocytosis and maintained numbers of resting microglia. In brain tissues from the 5xFAD mouse model of AD, levels of microglial BTK were elevated while in two gene expression datasets of post-mortem AD patient brain tissues, upregulation of BTK transcript was observed. Our study provides novel insights into the role of BTK in regulating microglial phagocytosis and uptake of synaptic structures and suggests that inhibiting microglial BTK may improve cognition in AD by preventing microglial activation and synaptic loss. Graphical Abstract Microglial-mediated synapse loss has been implicated in AD pathogenesis. Inhibition of BTK decreases activation of PLCγ2, a genetic risk factor in AD, and reduces microglial phagocytosis and uptake of synaptic structures. As such BTK inhibition may represent a therapeutic route to prevent microglial activation and synapse loss in AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.