ArticleActa neuropathologica2023
Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.
Article in Acta neuropathologica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 63 citations in OpenAlex.
- MD2-IN-1 restores microglial lysosomal function and attenuates amyloid pathology through TREM2-associated signaling in 5×FAD mice.Acta pharmacologica Sinica · 2026Article
- Intravital pH Imaging using the sensor ApHID Reveals Incomplete Lysosomal Acidification in Resident Meningeal Phagocytes.bioRxiv : the preprint server for biology · 2026Article
- Compartment-Specific Lysosomal Heterogeneity in Microglia Is Regulated by Adaptor Protein Complex-4.bioRxiv : the preprint server for biology · 2026Article
- Review
- Induced pluripotent stem cell-derived macrophages (iMacs) in translational medicine: Disease models, drug testing, and therapeutic applications.Molecular biology reports · 2026Review
- ThebioRxiv : the preprint server for biology · 2026Article
- Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.International journal of molecular sciences · 2026Review
- Brain-engrafted monocyte-derived macrophages from blood and skull-bone marrow exhibit distinct properties.Neuron · 2026Article
- Cocaine Upregulates Microglial Lipid Droplet Formation Through Increasing Lipid Synthesis Activity In Vitro and In Vivo.Biomolecules · 2026Article
- Phagocytosis and neuroinflammation: orchestrating central nervous system homeostasis, repair, and the resolution of inflammation.Trends in neurosciences · 2026Review
- TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.Nature communications · 2026Article
- Parkinson's disease: spatiotemporal regulation and therapeutic prospects of TREM2-mediated microglial responses.NPJ Parkinson's disease · 2026Review
- Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Alterations in the brain lipidome of Alzheimer's disease donors with rareBrain communications · 2026Article
- Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.Frontiers in nutrition · 2026Review
- The endo-lysosomal-lipid axis: bidirectional interactions between membrane trafficking dysfunction and lipid metabolic disorders.Frontiers in cell and developmental biology · 2026Review
- Microglia-Neuron Interactions in Alzheimer's Disease.Current neuropharmacology · 2026Review
- Differential downstream signaling in microglia lacking Alzheimer's-related TREM2 or its adaptor TYROBP/DAP12.Molecular neurodegeneration advances · 2026Article
- "Micro-managing" immune activation and protein turnover: microglial lysosomes in the context of health and disease.NPJ dementia · 2026Review
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
Corrections and comments
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Authors and funding
23 authors at 4 institutions in 3 countries.
Funding
Abstract
TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
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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.