TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy
Open accessAbstract
BACKGROUND: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. RESULTS: Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. CONCLUSIONS: Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies.
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TREM2, CD33, and CD22 play key roles in disease progression in AD patients and neurodegenerative mouse models.
“Most notably, emerging evidence from both AD patients and neurodegenerative mouse models has identified key roles for TREM2, CD33, and CD22 in disease progression (Bemiller et al., 2017; Krasemann et al., 2017; Malik et al., 2013; Pluvinage et al., 2019; Ulland et al., 2017; Wang et al., 2015).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Bemiller et al., 2017
Microglia can have differential effects on Alzheimer's disease pathology depending on the disease stage.
“These studies have led to the notion that microglia can have differential effects on AD pathology depending on the disease stage.”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [13]
Earlier studies on other microglial AD risk genes reported opposing effects on AD-related pathologies using various animal models at different ages.
“Earlier studies on other microglial AD risk genes reported opposing effects on AD-related pathologies using various animal models at different ages (8–14).”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [13]
Collectively, studies yielded disparate results regarding the effect of TREM2 on tau pathology and whether the effect is amyloid dependent or independent.
“Collectively, these studies yielded disparate results regarding the effect of TREM2 on tau pathology and whether the effect is amyloid dependent or independent.”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [12]
TREM2 ablation in the hTau model exacerbates tau hyperphosphorylation and aggregation.
“TREM2 ablation in the hTau model that expresses only human tau isoforms [16] exacerbates tau hyperphosphorylation and aggregation [12].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [12]
TREM2 loss-of-function studies have yielded conflicting outcomes in the context of tau pathology.
“TREM2 loss-of-function studies have also yielded conflicting outcomes in the context of tau pathology.”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [12]
TREM2 ablation significantly increased tau pathology in the hTau mouse model expressing all six isoforms of human tau.
“TREM2 ablation significantly increased tau pathology in the hTau mouse model expressing all six isoforms of human tau [12].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [12]
TREM2 deficiency in a hTau mouse model exacerbates tau phosphorylation and aggregation at the early disease stage.
“TREM2 deficiency in a hTau (expressing human MAPT but not endogenous mouse Mapt) mouse model exacerbates tau phosphorylation and aggregation at the early disease stage [126].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [126]
In tauopathies, microglia first sense and clear tau, but dysregulation of Cx3cr1 and Trem2 pathways leads to dysregulated host defense and neuroinflammatory damage.
“Microglia first sense and clear tau in an attempt to protect from tau toxicity, but dysregulation of microglial sensing and housekeeping pathways, such as the Cx3cr1 and Trem2 pathways, lead to dysregulation of the host-defense pathway, resulting in a neuroinflammatory response gone awry, causing neuronal damage and loss55–57.”
From Microglia in neurodegeneration (2018) · cites this paper as [57]
TREM2 deficiency enhances tau hyperphosphorylation at an early disease stage in htau mice and a mid-disease stage in P301S mice, but does not affect tau pathology at a late-disease stage in P301S mice.
“TREM2 deficiency is reported to enhance tau hyperphosphorylation at an early disease stage in htau mice65 and a mid-disease stage in P301S mice [G]66, but does not affect tau pathology at a late-disease stage in P301S mice67”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [65]
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Microglia, Trem2, and Neurodegeneration
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“However, the roles for Trem2 in pure tauopathy mouse models appear to be more complex and somewhat contradictory (Bemiller and others 2017; Sayed and others 2018).”
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TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo
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“The glial branches were measured using cross-sectional measurements of 2–10 randomly skeletonized and selected cells per animal (n = 4–6) using z-stack images in ImageJ, as previously described [12].”
BackgroundMethodSelf-citationDeletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways
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- Authors
- Bemiller, S. M., McCray, T. J., Allan, K., Formica, S. V., Xu, G., Wilson, G., Kokiko-Cochran, O. N., Crish, S. D., Lasagna-Reeves, C. A., Ransohoff, R. M., Landreth, G. E., & Lamb, B. T.
- Affiliations
- Cleveland Clinic (US)
- Indiana University Indianapolis (US)
- Case Western Reserve University (US)
- Cleveland Clinic Research (US)
- Northeast Ohio Medical University (US)
- Biogen (United States) (US)
- Corresponding author
- Bemiller, Shane M.
- Lamb, Bruce T.
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2017-10-16
- Volume
- 12
- Issue
- 1
- Pages
- 74-74
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC5644120
- OpenAlex
- W2765738520
- Cited by
- 299
- References
- 36
- Citations by year
- 2026: 15 · 2025: 32 · 2024: 21 · 2023: 37 · 2022: 61 · 2021: 30 · 2020: 45 · 2019: 28 · 2018: 26 · 2017: 3
- FWCI
- 21.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- 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
- U.S. Department of Defense (W81XWH-13-MRPRA-CSRA, W81XWH, W81XWH-13)
- Alzheimer's Association
- BrightFocus Foundation
- Indiana Clinical and Translational Sciences Institute (UL1TR001108)
- Cleveland Clinic
- National Institutes of Health (UL1TR001108, W81XWH, AG023012)
- National Institute on Aging (R01AG023012, F31AG050409, RF1AG051495, RF1AG050597)
- National Eye Institute (R01EY022358)
- National Institute of General Medical Sciences (T32GM007250)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, tau pathology, tau hyperphosphorylation, tau aggregation, tauopathy, Alzheimer's disease, late-onset Alzheimer's disease, microglia, neuronal stress, humanized mice, MAPT
- MeSH terms
- Animals, Disease Models, Animal, Humans, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Protein Kinases, Receptors, Immunologic, Signal Transduction, tau Proteins, Microglia, Tauopathies, Mice
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