Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

Meilandt, William J.; Ngu, Hai; Gogineni, Alvin; Lalehzadeh, Guita; Lee, Seung-Hye; Srinivasan, Karpagam; Imperio, Jose; Wu, Tiffany; Weber, Martin; Kruse, Agatha J.; Stark, Kimberly L.; Chan, Pamela; Kwong, Mandy; Modrušan, Zora; Friedman, Brad A.; Elstrott, Justin; Foreman, Oded; Easton, Amy; Sheng, Morgan; Hansen, David V.

doi:10.1523/jneurosci.1871-19.2019

Cited by 122 publications

(143 citation statements)

References 101 publications

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“…These data confirm the model proposed by Keren-Shaul et al 10 in which Tyrobp and Apoe transcripts are increased first, and neither transcription event requires the presence of Trem2. Moreover, Meilandt et al 48 recently reported that microglial APOE expression was not reduced, but, on the contrary, was increased in PS2APP;Trem2 -/when compared with microglial APOE expression in PS2APP mice. In that same study, they also analyzed the expression profiles of FACS-purified microglia from 5xFAD mice either in the presence or absence of Trem2 and showed a two-fold reduction in Apoe in one dataset (GSE132508) 10,48 but no reduction at all in the other (GSE65067) 48,49 .…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, Meilandt et al 48 recently reported that microglial APOE expression was not reduced, but, on the contrary, was increased in PS2APP;Trem2 -/when compared with microglial APOE expression in PS2APP mice. In that same study, they also analyzed the expression profiles of FACS-purified microglia from 5xFAD mice either in the presence or absence of Trem2 and showed a two-fold reduction in Apoe in one dataset (GSE132508) 10,48 but no reduction at all in the other (GSE65067) 48,49 . However, Parhizkar et al 50 reported that the absence of functional TREM2 reduces plaque-associated APOE.…”

Section: Discussionmentioning

confidence: 97%

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Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

Audrain

Haure‐Mirande

Mleczko

et al. 2020

Preprint

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Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer's disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgfb and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-beta deposits. Conversely, microglial Apoe mRNA level was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

Audrain

Haure‐Mirande

Mleczko

et al. 2020

Preprint

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“…In previous reports in DAP12KO mice, a reduced microglial increase after spinal nerve transection (Kobayashi et al, 2016) was found. Also, TREM2KO mice showed reduced microglia proliferation during homeostasis and after injury (Cantoni et al, 2015;Poliani et al, 2015;Zheng et al, 2017), and impaired proliferation was observed in AD mouse models without TREM2 or harboring dysfunctional TREM2 variants (Jay et al, 2017a;Cheng-Hathaway et al, 2018;Meilandt et al, 2020). On the other hand, some authors demonstrated that lack of TREM2 did not affect microglia proliferation in microglial cell cultures (Noto et al, 2010) or after spinal nerve FIGURE 14 | Temporal pattern of TREM2 expression in microglial cells in mice with astrocyte-targeted overexpression of IL-6 (GFAP-IL6Tg) or IL-10 (GFAP-IL10Tg) compared to their corresponding wild-type (WT) after PPT and FNA.…”

Section: Trem2+ Cells Expressed Markers Related To Proliferation and mentioning

confidence: 99%

Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models

Manich

Gómez-López

Almolda

et al. 2020

Front. Cell. Neurosci.

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Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where de novo expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury.

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“…The improvement in cognition found above, together with the reported need for TREM2 in the clearance of Aβ plaques (39,46,47), prompted us to test whether there was an effect on any form of Aβ in the absence of TREM2. Thus, after cognitive testing, hippocampi were excised, and the soluble (Tris-buffered saline, TBS-soluble) and insoluble (Triton-X-100-soluble) Aβ fractions were analyzed by ELISA.…”

Section: Cognitive Improvement and Reduction Of Soluble Amyloid Beta mentioning

confidence: 99%

TREM2-independent neuroprotection is mediated by monocyte-derived macrophages in a mouse model of Alzheimer’s disease

Dvir-Szternfeld¹,

Castellani²,

Arad³

et al. 2020

Preprint

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The contributions of disease-associated microglia (DAM) and infiltrating monocyte-derived macrophages (MDM) to Alzheimer’s disease (AD) are still controversial. Here, using Trem2−/−5xFAD DAM-deficient mice, we addressed this issue by targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, shown to modify AD via MDM recruitment. Treating Trem2−/−5xFAD mice resulted in cognitive improvement, rescue of synapses, and reduction of soluble-amyloid beta (Aβ)1−42, with no effect on insoluble Aβ1−42. In Trem2+/+5xFAD mice, the treatment enhanced cognitive performance, led to elevation in DAM levels, and reduced insoluble Aβ1−42. Single-cell RNA-sequencing revealed that MDM, derived from both Trem2−/− and Trem2+/+ 5xFAD mouse brains, express a unique set of scavenger receptors and anti-inflammatory genes. Eliminating monocytes abrogated the beneficial effect of anti-PD-L1. The results highlight the need for MDM for neuroprotection even when microglia are fully activated, and demonstrate that their activity occurs through a TREM2-independent mechanism, with the potential to overcome TREM2 polymorphism in patients.

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Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

Cited by 122 publications

References 101 publications

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models

TREM2-independent neuroprotection is mediated by monocyte-derived macrophages in a mouse model of Alzheimer’s disease

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