Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia
Open accessAbstract
Together with its adaptor protein, the adaptor protein of 12 kDa also known as KARAP and TYROBP (DAP12), triggering r (TREM2) is a stimulatory membrane receptor of the immunoglobulin/lectin‐like superfamily, well known in myeloid cells. In humans, however, loss‐of‐function mutations of TREM2/DAP12 leave myeloid cells unaffected but induce an autosomal recessive disease characterized, together with bone cysts, by a spectrum of pathological lesions in the cortex, thalamus and basal ganglia with clinical symptoms of progressive dementia (polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy). Nothing was known about the role of TREM2/DAP12 in brain cell biology and physiology. By confocal immunocytochemistry we demonstrate that, in both human and mouse cerebral cortex, TREM2/DAP12, strongly expressed by microglia, is also present in a fraction of neurons but not in astrocytes and oligodendrocytes. In contrast, in the hippocampal cortex TREM2‐expressing neurons are rare. Both in neurons and microglia the receptor appears to be located mostly intracellularly in a discrete compartment(s) partially coinciding with (or adjacent to) the Golgi complex/trans‐Golgi network. Four nerve cell lines were identified as expressing the intracellular receptor system. In living human microglia CHME‐5 and glioblastoma T98G cells, activation of TREM2 by its specific antibody induced [Ca 2+ ] i responses, documenting its surface expression and functioning. Surface expression of TREM2, low in resting CHME‐5 and T98G cells, increases significantly and transiently (60 min) when cells are stimulated by ionomycin, as revealed by both surface biotinylation and surface immunolabeling. Our results provide the first information about the expression, distribution (mostly intracellular) and functioning of TREM2/DAP12 system in nerve cells, a necessary step in the understanding of the cellular mechanisms affected in polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy.
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Recent studies suggested TYROBP-mediated signaling is involved in multiple important functions as aggregating Aβ activates microglia, including enhanced phagocytosis of damaged neurons and suppression of inflammatory responses, as well as neuronal pruning activity.
“Recent studies suggested TYROBP-mediated signaling is involved in multiple important functions as aggregating Aβ activates microglia, including enhanced phagocytosis of damaged neurons [56, 90] and suppression of inflammatory responses [94], as well as neuronal pruning activity [56].”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [94]
The Abstract and Effects of cell stimulation (pages unavailable) identify TYROBP/DAP12 in microglia and report signaling after antibody activation of TREM2. They do not link that signaling to phagocytosis of damaged neurons, neuronal pruning, or activation by aggregated Aβ—the functions and context for which this source is cited. The separate claim about suppression of inflammatory responses is cited to [94], not this paper. (LLM, conf=0.82)
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- Authors
- Sessa, G., Podini, P., Mariani, M., Meroni, A., Spreafico, R., Sinigaglia, F., Colonna, M., Panina, P., & Meldolesi, J.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Washington University in St. Louis (US)
- Corresponding author
- Meldolesi, Jacopo
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2004-11
- Volume
- 20
- Issue
- 10
- Pages
- 2617-2628
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W2130103159
- Cited by
- 165
- References
- 4
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 8 · 2021: 12 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 14 · 2016: 15 · 2015: 17 · 2014: 19 · 2013: 11 · 2012: 3
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, DAP12, microglia, neurons, Golgi apparatus, trans-Golgi network, calcium signaling, receptor activation, cell surface expression, neuroinflammation
- MeSH terms
- Triggering Receptor Expressed on Myeloid Cells-1, Golgi Matrix Proteins, Animals, Antibodies, Brain, Calcium, Cerebral Cortex, Dementia, Drug Interactions, Epilepsy, Flow Cytometry, Glial Fibrillary Acidic Protein, Glioblastoma, Golgi Apparatus, Humans, Immunohistochemistry, Ionophores, Membrane Glycoproteins, Membrane Proteins, Mice, Inbred BALB C, Neuroblastoma, Neurons, Phosphopyruvate Hydratase, Receptors, Immunologic, Subacute Sclerosing Panencephalitis, Time Factors, Ionomycin, Microscopy, Immunoelectron, Microglia, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Myeloid Cells, Cell Line, Tumor, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Mice
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