Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Open accessAbstract
Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer’s disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive. Methods: Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes. Results: Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia. Conclusion: Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes. Graphical abstract:
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Microglia or macrophage uptake of tau does not depend on TREM2 expression.
“in vitro experiments suggest that microglia or macrophage uptake of tau does not depend on TREM2 expression [39,43].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [43]
TREM2 deletion promotes tau trafficking to late endosome/pre-exosomal compartments.
“they suggested that TREM2 deletion promotes tau trafficking to late endosome/pre-exosomal compartments [43].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [43]
TREM2 deletion enhanced tau spreading from the medial entorhinal cortex (MEC) to the hippocampal dentate gyrus (DG) in a model using AAV expression of P301L tau.
“a recent study using the adeno-associated virus (AAV) expression of P301L tau showed that TREM2 deletion enhanced tau spreading from the medial entorhinal cortex (MEC) to the hippocampal dentate gyrus (DG) [43].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [43]
TREM2 deletion aggravates tau spreading, possibly through microglial extracellular exosomes.
“The authors demonstrated that TREM2 deletion aggravates tau spreading, possibly through microglial extracellular exosomes.”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [43]
TREM2 deficiency exacerbates pathological tau propagation via microglial exosomes.
“Furthermore, Zhu et al. reveal that TREM2 deficiency exacerbates pathological tau propagation via microglial exosomes [196].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [196]
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- Authors
- Zhu, B., Liu, Y., Hwang, S., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Chongqing Medical University (CN)
- Corresponding author
- Xu, Huaxi
- Huang, Timothy Y.
- Venue
- Molecular Neurodegeneration
- Published
- 2022-09-02
- Volume
- 17
- Issue
- 1
- Pages
- 58-58
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC9438095
- OpenAlex
- W4294169024
- Cited by
- 127
- References
- 69
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 35 · 2023: 26 · 2022: 3
- FWCI
- 15.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (R21 AG070676, RF1 056130)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- TREM2, tau pathology, Alzheimer's disease, microglia, exosomes, tau propagation, tau seeding, medial entorhinal cortex, hippocampus, memory impairment, TREM2 knockout mice
- MeSH terms
- Alzheimer Disease, Animals, Membrane Glycoproteins, Receptors, Immunologic, Microglia, Mice, Knockout, Proteomics, Mice, Exosomes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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