Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

Lee, Seung-Hye; Meilandt, William J.; Xie, Luke; Gandham, Vineela D.; Ngu, Hai; Barck, Kai; Rezzonico, Mitchell G.; Imperio, Jose; Lalehzadeh, Guita; Huntley, Melanie A.; Stark, Kimberly L.; Foreman, Oded; Carano, Richard A.D.; Friedman, Brad A.; Sheng, Morgan; Easton, Amy; Bohlen, Christopher J.; Hansen, David V.

doi:10.1016/j.neuron.2021.02.010

Cited by 151 publications

(162 citation statements)

References 79 publications

(109 reference statements)

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“…This is very surprising since chronically activated microglia, as observed in PGRN loss-of-function models and mouse models for amyloid and tau pathology would have been expected to exert significant damage within the brain, for example by induction of the inflammasome (Heneka et al, 2018). However, our findings together with those by Lee et al (Lee et al, 2021) rather suggest that TREM2 dependent chronic activation is protective, which may have implications for therapeutic attempts employing modulation of TREM2 activity by agonistic antibodies (Deczkowska et al, 2020;Lewcock et al, 2020). In that regard the nomenclature used for describing diverse microglial states, namely homeostatic, disease associated, and hyperactivated, may also be reconsidered.…”

Section: Discussionmentioning

confidence: 73%

“…Consistently, fully activated DAM2 microglia were recently described to be particularly protective in a mouse model for amyloidosis and tau pathology (Lee et al, 2021). This is very surprising since chronically activated microglia, as observed in PGRN loss-of-function models and mouse models for amyloid and tau pathology would have been expected to exert significant damage within the brain, for example by induction of the inflammasome (Heneka et al, 2018).…”

Section: Discussionmentioning

confidence: 91%

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Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Reifschneider

Robinson

et al. 2021

Preprint

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GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 91%

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Reifschneider

Robinson

et al. 2021

Preprint

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“…Expression profiling of DAM has revealed the upregulation of genes involved in lipid metabolism (most notably, ApoE) and apparently reduced capacity for engulfment, phagocytosis and degradation ( Krasemann et al, 2017 ; Ulland et al, 2017 ). Although often associated with degenerative processes ( Deczkowska et al, 2018 ), it has been reported to be involved in either protective processes (such as amyloid plaque compaction in AD, debris clearing in stroke or myelin damage; Cignarella et al, 2020 ; Meilandt et al, 2020 ; Lee et al, 2021 ) or detrimental processes ( Götzl et al, 2019 ) depending on the pathological condition. On the other hand, CD169 expression characterizes actively phagocytosing cells ( O’Neill et al, 2013 ); CD169 is normally not expressed in microglia but a distinct population of CD169 + microglia has been associated with active phagocytosis of myelin and it is highly pathogenic in EAE models ( Bogie et al, 2018 ; Ostendorf et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although the induction of a DAM-like phenotype by AMX in the context of SWI appears detrimental, as measured by the larger astrocytic scar, the induction of a DAM phenotype as been hypothesized to be beneficial in the context of Alzheimer Disease (AD; Lewcock et al, 2020 ). In AD, genetic variants reducing TREM2 signaling causes the reduced induction of DAM, which normally surround amyloid plaques and display active phagocytosis and lipid metabolism, with beneficial consequences on synaptic loss, amyloid peptides burden and dystrophic dendrites ( Meilandt et al, 2020 ; Lee et al, 2021 ). Since TREM2 with reduced signaling appear to be risk factors for AD and are associated with incomplete DAM induction, strategies have been developed to upregulate TREM2 signaling using genetic (e.g., Lee et al, 2018 ) or antibody ( Cignarella et al, 2020 ; Lewcock et al, 2020 ) approaches.…”

Section: Discussionmentioning

confidence: 99%

Acute TBK1/IKK-ε Inhibition Enhances the Generation of Disease-Associated Microglia-Like Phenotype Upon Cortical Stab-Wound Injury

Rehman

Tar

Olamide

et al. 2021

Front. Aging Neurosci.

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Traumatic brain injury has a poorer prognosis in elderly patients, possibly because of the enhanced inflammatory response characteristic of advanced age, known as “inflammaging.” Recently, reduced activation of the TANK-Binding-Kinase 1 (Tbk1) pathway has been linked to age-associated neurodegeneration and neuroinflammation. Here we investigated how the blockade of Tbk1 and of the closely related IKK-ε by the small molecule Amlexanox could modify the microglial and immune response to cortical stab-wound injury in mice. We demonstrated that Tbk1/IKK-ε inhibition resulted in a massive expansion of microglial cells characterized by the TMEM119+/CD11c+ phenotype, expressing high levels of CD68 and CD317, and with the upregulation of Cst7a, Prgn and Ccl4 and the decrease in the expression levels of Tmem119 itself and P2yr12, thus a profile close to Disease-Associated Microglia (DAM, a subset of reactive microglia abundant in Alzheimer’s Disease and other neurodegenerative conditions). Furthermore, Tbk1/IKK-ε inhibition increased the infiltration of CD3+ lymphocytes, CD169+ macrophages and CD11c+/CD169+ cells. The enhanced immune response was associated with increased expression of Il-33, Ifn-g, Il-17, and Il-19. This upsurge in the response to the stab wound was associated with the expanded astroglial scars and increased deposition of chondroitin-sulfate proteoglycans at 7 days post injury. Thus, Tbk1/IKK-ε blockade results in a massive expansion of microglial cells with a phenotype resembling DAM and with the substantial enhancement of neuroinflammatory responses. In this context, the induction of DAM is associated with a detrimental outcome such as larger injury-related glial scars. Thus, the Tbk1/IKK-ε pathway is critical to repress neuroinflammation upon stab-wound injury and Tbk1/IKK-ε inhibitors may provide an innovative approach to investigate the consequences of DAM induction.

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“…TREM2 limits the spreading of tau pathology. Recent evidence suggested that TREM2 limits tau pathology progression in an Aβ-dependent context in tau transgenic pR5 mice (73). In fact, Aβ has been shown to enhance tau pathology progression also in other models (77,78).…”

Section: Discussionmentioning

confidence: 99%

TREM2 Limits Progression of Deficits and Spreading of Tau Pathology in Mice

Feiten¹,

Au²,

Hummel³

et al. 2021

Preprint

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Background. Amyloid-β (Aβ) and tau form pathogenic lesions in Alzheimer’s disease (AD) brains. As ΑD clinically progresses, tau pathology propagates in a very distinct pattern between connected brain areas. The molecular mechanisms underlying this tau pathology spread remain largely unknown. Genome-wide association studies have identified polymorphisms in triggering receptor expressed on myeloid cells 2 ( TREM2 ) as genetic risk factors for AD and regulators of Aβ pathology-dependent tau propagation. Whether TREM2 contributes to neuron-to-neuron spreading of pathological tau remains unknown.Methods. Here, we crossed Trem2- deficient mice with P301S tau transgenic TAU58 mice and subjected the mice to behavioral testing and assessed neuropathology. Microglial activation states were determined using cytometry by of flight (CyTOF) and quantitative PCR. Tau spreading was assessed in vivo using tracing of focal tau expression.Results. Trem2 depletion significantly aggravated tau-induced early-onset motor and behavioural deficits. Neuropathologically, Trem2 reduction increased the number of hyperphosphorylated tau lesions in young TAU58 brains and reduced disease-associated microglia. Direct assessment of inter-neuronal spread of tau in vivo revealed significantly enhanced propagation of tau in the absence of Trem2 , suggesting that microglial TREM2 limits the progression of tau pathology in disease.Conclusion. Taken together, our data suggests that reduced TREM2 function accelerates the onset and progression of functional deficits and tau neuropathology in tau transgenic mice, which is - at least in part - due to increased tau spreading. Therefore, reduced TREM2 function may contribute to early AD by augmenting tau toxicity and its inter-neuronal propagation.

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Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

Cited by 151 publications

References 79 publications

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Acute TBK1/IKK-ε Inhibition Enhances the Generation of Disease-Associated Microglia-Like Phenotype Upon Cortical Stab-Wound Injury

TREM2 Limits Progression of Deficits and Spreading of Tau Pathology in Mice

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