The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

In the citing paper

“The DAM response is dependent on TREM2 and APOE, two major AD risk genes, in mouse models of AD and metabolic disease (Krasemann et al., 2017; Pimenova et al., 2017a).”

In the citing paper

“Krasemann et al. found that APOE can bind with the intracellular domain of TREM2 and switch microglia from a homeostatic phenotype to neurodegenerative phenotype in multiple neurodegenerative models including AD, indicating APOE-TREM2 pathway as a proinflammatory signaling.182”

In the citing paper

“Microglial accumulation at plaques and plaque-driven morphological and transcriptional responses depend on microglial surface receptor-mediated signalling8,12,13,29, which involves activation of the tyrosine kinase (SYK)9,30 and one of its key downstream targets (PLCγ2)31,32.”

In the citing paper

“Addressing this question directly, more recent studies combining single-cell transcriptomics with fate-mapping studies, in both animals and humans, have revealed that some of the macrophage subsets identified during disease are activation states of tissue resident macrophages (35–38).”

In the citing paper

“These pathways highlight how neuronal and glial interactions modulate microglial activity through Apoe, App, Trem2, and Lrp1 [Krasemann et al., 2017; Lin & Holtzman 2024; Shinohara et al., 2017].”

In the citing paper

“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).”

In the citing paper

“This pathway regulates the switch from a homeostatic to a neurodegenerative molecular signature by inducing miR155 via apolipoprotein E (APOE) signaling,48”

In the citing paper

“This supports a protective role for the DAM/MGnD microglial phenotype, with TREM2-dependent functions potentially required initially to prevent seeding of plaques, whilst later enhancing the consolidation of Aβ into compact aggregates to protect neurons from Aβ-induced injury.”

In the citing paper

“AD patients carrying mutations in TREM2 genes display less compact Aβ plaques and fewer plaque-associated microglia but enhanced tau pathology and neuritic plaques [191, 361]”

In the citing paper

“Single-cell RNA sequencing identified gene signatures characteristic of protective and dysfunctional microglial subpopulations in AD9,10.”

In the citing paper

“Thus, DAM and MGnD are best understood not as inherently beneficial or harmful categories, but as context-dependent responses whose net effect depends on disease stage, brain region, and the balance between phagocytic containment and inflammatory injury.”

In the citing paper

“Existing categories such as DAM and MGnD have already shown that microglia can enter disease-linked states, but they do not fully explain how protective immune regulation is achieved within the Alzheimer’s brain.”

In the citing paper

“Interestingly, the phenotype of microglia we observed in HDLS is similar to that found in an SOD1 ALS mouse model and in multiple sclerosis patients, in which the molecules associated with the homeostatic microglial phenotype (e.g., P2RY12, CSF-1R) are down-regulated and inflammatory markers are up-regulated [24, 57].”

In the citing paper

“CD11c+ microglia are known to increase in chronic inflammatory and neurodegenerative conditions as well as during development [76–83]”

In the citing paper

“Our findings in humans were validated in mice with inactivated Plcg2 expression (PLCG2 inact), which reduced expression levels of AD-associated microglial genes [39, 40], including CLEC7A, C3, and PIK3R5, in comparison with expression levels of these genes in WT mice.”

In the citing paper

“The existence of DAM in mice and humans has recently been confirmed in tauopathy AD models (26, 27), aging (27, 28), and other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) (29) and multiple sclerosis (30).”

In the citing paper

“Ligation of the Trem2 receptor by ApoE is sufficient to promote phagocytosis in TREM2-expressing microglial (brain-resident macrophage) cells and, in turn, activates Apoe RNA expression,89”

In the citing paper

“High-confidence Trem2+ monocytes were identified by expression of known TREM2+ monocyte markers (TREM2, APOE, CSF1R81,89), identified by gene-weighted density estimation implemented in the Nebulosa package for R.78”

In the citing paper

“It has been demonstrated that this in vivo model induces a well-defined microglial proinflammatory phenotype different to the recently characterized molecular signature of disease-associated microglia (Bodea et al., 2014; Krasemann et al., 2017).”

In the citing paper

“In fact, these aggregated forms play leading roles in driving main pathogenic events in these neurodegenerative diseases with the active involvement of highly activated microglia, more recently referred to as disease-associated microglia (Krasemann et al., 2017) (Keren-Shaul et al., 2017) (Mathys et al., 2017).”

In the citing paper

“We also found that microglial TET2 is upregulated in vivo in two-well defined models of microglia polarization; in a neuroinflammatory mouse model induced by repeated intraperitoneal injections of LPS (Krasemann et al., 2017; Bodea et al., 2014), and in AD, including human patients and transgenic mice (5xFAD).”

In the citing paper

“Twenty one core genes associated with XO4+/XO4− phenotype were identified as altered in several studies of neurodegenerative disease-associated microglia (DAM)13,14,32”

In the citing paper

“The XO4+-associated gene expression signature identified here partially overlaps with other microglia signatures obtained from aged, APP/PS1, 5xFAD or tau model mice13,14,31–33”

In the citing paper

“Recent studies13,14 identified a novel microglial phenotype near Aβ plaques that was dependent on Trem2 and Apoe in two mouse models of AD.”

In the citing paper

“Studies have shown that plaque-adjacent microglia in human post mortem AD brains upregulate LPL13 and downregulate P2RY1214”

In the citing paper

“We demonstrate here, in agreement with previous findings (Keren-Shaul et al., 2017; Krasemann et al., 2017), that ARMs induce Apoe expression up to 27-fold, compared to homeostatic microglia.”

In the citing paper

“Dysregulation of the TREM2/ APOE axis has been implicated in heightened neuroinflammation, neuronal injury, and complement-mediated synaptic clearance, representing a critical therapeutic target in AD pathology (68).”

In the citing paper

“In line with other studies, we observe an upregulation in DAM genes (i.e., Cst7, Apoe, Ctsb, Ctsd, Ctss, and Psen1) and downregulation in homeostatic genes (P2ry12, Tmem119, and Csf1r) in 5xFAD compared to WT mice [48, 57, 58].”

In the citing paper

“Together with triggering receptor expressed on myeloid cells 2 (TREM2), APOE has also been shown to regulate microglial response to Aβ plaques and neurofibrillary tangles in AD as well as in other neurodegenerative diseases150.”

In the citing paper

“apoE reduction or depletion attenuates neuroinflammation and alleviates pathological changes in various mouse models of amyloid and tau pathology”

In the citing paper

“carriage of the E4 allele is associated with increased neuroinflammation and metabolic disturbances within neurons and glial cells (Krasemann et al., 2017)”

In the citing paper

“MGnD (p < 0.05 relative to TG-Abi3-Gngt2+/−) [25]”

In the citing paper

“The analysis revealed 5 discrete microglial clusters, each representing a different microglial state, including previously characterized homeostatic, transitioning, activated plaque-responsive (Act), and interferon (IFN)-responsive microglial subsets 1,3,33 (Figure 7A and 7B).”

In the citing paper

“Shared DEGs from both datasets were associated with enhanced IFN signaling, indicating the IFN pathway as an early response in microglia reacting to remote pathological changes 7,34 (Fig 1h,i).”

In the citing paper

“In the current work, we focus on cholesterol 25-hydroxylase (Ch25h), which is upregulated in DAM only when both Apoe and Trem2 are present (Krasemann et al., 2017; Zhou et al., 2020).”

In the citing paper

“A two-stage activation of microglial phenotype, switching from a homeostatic state to DAM, has been shown to be Apoe and Trem2 dependent (Krasemann et al., 2017; Deczkowska et al., 2018; Keren-Shaul et al., 2017).”

In the citing paper

“Single-cell transcriptomic analysis carried out in AD human and AD mouse model brain tissue have identified unique signatures of gene expression in microglia in physical proximity to amyloid plaques and tau aggregates, termed DAM (Keren-Shaul et al., 2017; Krasemann et al., 2017; Zhou et al., 2020).”

In the citing paper

“Cluster 1 is characterized by high expression of mRNA for markers (e.g., Apobec, Apoe, Axl, Cd9, and Lpl) typical of the transcriptomic signature referred to as microglial neurodegenerative (MGnD) or DAM (Fig. 8 D and Table S9) (Deczkowska et al., 2018; Keren-Shaul et al., 2017; Krasemann et al., 2017).”

In the citing paper

“In aging or neurodegeneration, mouse microglia adopt Apoe and Trem2-dependent disease-associated or neurodegenerative microglia phenotype (DAM, MGnD), upregulating Apoe (Keren-Shaul et al., 2017; Krasemann et al., 2017).”

In the citing paper

“In studies of microglial activation in amyloid models, MHC-II and Spp1 were elevated in an advanced activated state (activated response microglia (ARM)) that corresponded with high levels of Apoe expression (Krasemann et al., 2017; Sala Frigerio et al., 2019).”

In the citing paper

“In the context of CNS damage resulting from Aβ, tau, SOD-1, or other pathologies, apoE is strongly upregulated in microglia coincident with the DAM or MGnD phenotype (Butovsky et al., 2015; Keren-Shaul et al., 2017; Krasemann et al., 2017; Parhizkar et al., 2019; Shi et al., 2017).”

In the citing paper

“In the central nervous system (CNS), ApoE is primarily secreted by astrocytes under homeostatic conditions with microglia upregulating ApoE secretion under multiple disease conditions [18–20, 93–95].”

In the citing paper

“In the context of AD pathology, such as amyloid-β (Aβ) plaques or tauopathy, microglia strongly upregulate APOE expression (4, 11).”

In the citing paper

“Second, in case–control frameworks, we demonstrate with our reanalysis of two examples from the literature that, without knowledge of the presence of the exAM signature, it can result in spurious identification of the exAM signature as differentially expressed (Supplementary Note 4)41,42,69,70.”

In the citing paper

“These opposing states are accompanied by broad changes in gene expression12–17, suggesting that defined transcriptional programs in microglia may govern their neuroprotective or neurotoxic functions.”

In the citing paper

“Extensive work has characterized microglial receptor TREM2 as influential in driving microglial acquisition of the DAM transcriptome (Keren-Shaul et al., 2017; Krasemann et al., 2017; Wang et al., 2015).”

In the citing paper

“Recently, it has been shown that several subsets of microglia with unique molecular and functional phenotypes exist in the healthy, aged, and degenerating brain3–5.”

In the citing paper

“Support for beneficial outcomes associated with maintenance and/or restoration of homeostatic functions of microglia comes from the numerous studies targeting the members of this pathway, including Trem2,48,50–52 Tyrobp,53,54 and miR155.41,55”

In the citing paper

“P2RY12 is considered a homeostatic microglia marker because of its downregulation in neurogenerative and neuroinflammatory models, including amyotrophic lateral sclerosis, AD (Table 5) and MS (Table 6) [174, 179, 191, 214], which have been more extensively investigated than encephalitis (Table 3) and stroke (Table 4).”

In the citing paper

“Recent transcriptomic studies have identified a subset of microglia that adopt unique transcriptional and functional signatures, termed ‘disease-associated microglia’ (DAM) [179] or ‘microglial neurodegenerative’ (MGnD) phenotype during neurodegeneration [191]”

In the citing paper

“in mice with cerebral amyloidosis, genetic ablation of TREM2 abrogated the MGnD phenotype and reduced the microglial response to plaques [191]”

In the citing paper

“mechanistic studies of the TREM2–APOE pathway showed that microglial phenotypes in neurodegeneration are actively regulated transcriptional programs, not passive responses to tissue damage [16].”

In the citing paper

“A neurodegenerative disease-associated microglial signature has also been described, termed MGnD [24].”

In the citing paper

“The two disorders may lie on a disease spectrum, possibly converging via the TREM2-APOE pathway previously reported to be associated with MGnD [24].”

In the citing paper

“MGnD represents an induced inflammatory signature mediated by the triggering receptor expressed on myeloid cells 2 (TREM2)-apolipoprotein E (APOE) pathway, which suppresses the M0 signature.”

In the citing paper

“For example, Trem2, a known AD risk gene expressed in microglia (Krasemann et al., 2017; Sims et al., 2017), is present in Signatures A and C.”

In the citing paper

“Recent findings point to microglia heterogeneity in neurodegeneration [36, 38].”

In the citing paper

“The transcriptional shift microglia undergo in response to Aβ is thought to be at least partially dependent on TREM2 expression, 33 , 39”

In the citing paper

“In recent years, a critical role for transcriptional changes in microglial activation has been highlighted, and unique RNA signatures are used to identify distinct microglial subpopulations [5, 52].”

In the citing paper

“In the central nervous system, APOE is upregulated in MGnD 4,5 .”

In the citing paper

“We identified that neurodegenerative microglia (MGnD) 4 , also referred to as disease-associated microglia 5 , are regulated by the reciprocal suppression of transforming growth factor-β (TGFβ) and induction of apolipoprotein E (APOE) signaling in different neurodegenerative models, including AD 4 .”

In the citing paper

“Additional characterization of microglia by analyzing the acute response to neurodegeneration via intracranial injection of apoptotic neurons 4 showed upregulation of antigen presentation- and IFNγ signaling-related genes in Itgb8 -cKO mice compared to in control mice (Extended Data Fig. 8e-g and Supplementary Table 8).”

In the citing paper

“Single-cell transcriptional profiling of cGAS gain-of-function mice further reveals that, beyond type I IFNs, cGAS activation alone triggers a core microglial gene expression program that is shared between many neurodegenerative disease states and during ageing38–40,51.”

In the citing paper

“The potential involvement of TET2 in the recent characterized disease-associated microglia (Keren Shaul et al., 2017; Krasemann et al., 2017) is deduced from analysis of both AD transgenic mice and human AD tissues in which TET2 was highly upregulated specifically in amyloid plaque-associated microglia.”

In the citing paper

“our analysis identified 2031 (out of 2810, 72.3%) genes associated with XO4+ microglia that were not reported in previous RNA-sequencing studies of microglia in neurodegeneration13,14,33”

In the citing paper

“APOE is involved in the regulation of DAMs and the microglial response to amyloid [57, 64–66].”

In the citing paper

“Krasemann et al. showed that the DAM (DAM/MGnD) signature is dependent on the TREM2-APOE pathway [57].”

In the citing paper

“We performed snRNA-seq to identify cell type-specific transcriptomic changes, and discovered that E3S/S reduced cGAS-STING-IFN signaling in microglia without affecting disease-associated microglial signatures (DAMs)17 or microglial neurodegenerative phenotype (MGnD)18.”

In the citing paper

“We performed snRNA-seq to identify cell type-specific transcriptomic changes, and discovered that E3S/S reduced cGAS-STING-IFN signaling in microglia without affecting disease-associated microglial signatures (DAMs)17 or microglial neurodegenerative phenotype (MGnD)18.”

In the citing paper

“its expression is markedly upregulated by reactive microglia in the brains of individuals with AD96,150.”

In the citing paper

“This upregulation is a key element of a conserved transcriptional signature of reactive microglia that has been found in multiple neurodegenerative diseases150,151.”

In the citing paper

“microglia-derived apoE was shown to cell-autonomously promote microglial activation towards the neurodegenerative “MGnD/DAM” phenotype (Krasemann et al., 2017).”

In the citing paper

“Apoe is one of the most upregulated genes in a subset of microglia with neurodegenerative phenotype in amyloid mouse models”

In the citing paper

“The phenotype of disease-associated microglia (DAM) is dependent on the TREM2-apoE pathway, and deletion of apoE might prevent DAM development”

In the citing paper

“In AD mouse models, there is a subset of microglia exhibiting a neurodegenerative/disease-associated phenotype characterized by upregulation of pro-inflammatory genes”

In the citing paper

“In contrast, microglia can significantly upregulate APOE expression as part of their DAM (Disease Associated Microglia) response to the amyloid plaques (Chen et al, 2020; Keren-Shaul et al, 2017; Krasemann et al, 2017; Sala Frigerio et al, 2019).”

In the citing paper

“The DAM response is dependent on APOE expression (Krasemann et al, 2017; Sala Frigerio et al, 2019) but it was thought that APOE expression in microglia was essential.”

In the citing paper

“These genes are also reported to be associated with pathologic signatures in AD, most notably DAM and MGnD [24, 25] and PIG [21]”

In the citing paper

“Moreover, two recent studies have reported a phenotypic change of microglia in neurodegenerative diseases from homeostatic to disease-associated microglia (DAM) [62, 63].”

In the citing paper

“Apoe is one of the most striking TREM2-dependent damage-associated microglia genes”

In the citing paper

“microglial responses in the Apoe–/– phenocopy those of Trem2–/– in specific paradigms, such as phagocytosis of apoptotic neurons”

In the citing paper

“Previous in vitro and in vivo studies suggested a role for apoE in mediating TREM2-dependent phagocytosis of apoptotic neurons (Atagi et al., 2015; Krasemann et al., 2017).”

In the citing paper

“However, in the setting of brain injury or neurodegeneration, APOE expression is strongly upregulated in microglia (Krasemann et al., 2017).”

In the citing paper

“Selective removal of APOE from microglia attenuated facial motor neuron death after axotomy, indicating that microglial apoE expression plays a key role in promoting the DAM/MGnD transcriptional state (Krasemann et al., 2017).”

In the citing paper

“Selective removal of APOE from microglia attenuated facial motor neuron death after axotomy, indicating that microglial apoE expression plays a key role in promoting the DAM/MGnD transcriptional state (Krasemann et al., 2017).”

In the citing paper

“many of the activated “disease-associated microglia” (DAM) signatures observed in 5xFAD microglia (Keren-Shaul, Spinrad et al. 2017) are also observed in other models of neurodegeneration (neurodegenerative microglia, MGnD) including amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS) (Krasemann, Madore et al. 2017).”

In the citing paper

“In the context of neurodegeneration, microglia strongly upregulate ApoE expression (4, 11).”

In the citing paper

“Cathepsin B signal appears punctate when localized to the lysosomes, whereas the signal becomes diffuse (and perhaps below the limit of detection by immunostaining) when localized to the cytosol upon LMP44–46.”

In the citing paper

“Based on the previous literature42,43,46, we reasoned that cathepsin B leaking from the destabilized lysosomes may mediate the NLRP3 inflammasome activation upon SHIP1 inhibition11.”

In the citing paper

“The intracellular signaling pathway downstream TREM2 is complex and involves many molecules in addition to PLCG2, including Syk and PI3K. 32 , 33 , 35 , 43 , 58 , 59”

In the citing paper

“TREM2 is one of the key receptors modulating PLCγ2 activity [12, 36, 37].”

In the citing paper

“SHIP1 protein expression was identified in plaque-associated microglia of 5xFAD mice, with phagocytic microglia showing a reduction of Inpp5d expression compared to non-phagocytic microglia [168, 169].”

In the citing paper

“Validation data for all commercial antibodies are available on the manufacturer's website including previously published papers as below:”

In the citing paper

“Based on publicly available data in this model (Krasemann et al., 2017), we focused on the expression of the two highest induced genes upon repeated systemic LPS injections, Ptgs2 and Cybb (also known as Cox2 and Nox-2 respectively), where both genes are considered as proinflammatory mediators (Alhadidi and Shah, 2018; Benusa et al., 2017).”

In the citing paper

“It is noteworthy to mention that in different single cell RNAseq of microglia in different AD models, the expression of TET2 was found not to be upregulated (Krasemann et al., 2017) (Keren-Shaul et al., 2017) (Mathys et al., 2017).”

In the citing paper

“It is interesting to note that Hif1a is not a signature gene described by Krasemann et al.14”

In the citing paper

“In these studies, CH25H has been identified as one of the upregulated genes featured in the DAM subcluster, which is characterized by expression of typical microglial markers, Iba1, Cst3, and Hexb, and upregulation of genes involved in phagocytosis and lipid metabolism, including Apoe, Ctsd, Lpl, Tyrobp, and Trem2 (reviewed by Deczkowska, et al. 2018) [64].”

In the citing paper

“These controversial outcomes highlight a complex dual role of microglia also observed in other brain diseases [54,55,56] and might be attributed to the fact that the total removal of microglia might be harmful, whereas targeting specific microglia activation states later in disease might prolong survival time.”

In the citing paper

“Fittingly, we found that the loss of the homeostatic signature is especially severe in prion diseases compared to other neurodegenerative conditions [47,55].”

In the citing paper

“The loss of homeostatic microglial proteins is visible in immunofluorescence double-staining of IBA1 and TMEM119 in terminally sick mice and mock-infected healthy control brains, and shows the reciprocal regulation of both proteins in prion disease (Figure 5A) [55,73,88,89,90,91].”

In the citing paper

“We and others have identified a disease-specific microglia signature that is commonly dysregulated in brain diseases including AD [55,101].”

In the citing paper

“Such activated microglia, which have been referred to as disease-associated microglia (DAM), has a transcriptional signature quite distinct from that of homeostatic microglia that markedly declines in mouse models of AD10,11,12.”

In the citing paper

“These results were highly concordant between the 7-month- and 15-month-old datasets (Fig. 2d) and with previously published single cell RNA-seq data of sorted microglia10,11,12.”

In the citing paper

“Altogether, these data suggest that the signature of human microglia in AD is quite distinct from that of DAM in the 5XFAD model10,11: it is reminiscent of the reactive phenotype observed in PNI and may be in part instructed by IRF8.”

In the citing paper

“In mice accumulating Aβ, microglia swap their “homeostatic” signature with a DAM signature that is partially Trem2-dependent10,11.”

In the citing paper

“Several genetically distinct subtypes of microglia have been discovered as they respond to signals or challenges in the brain microenvironment, namely homeostatic microglia and “disease-associated microglia” (DAM) or “microglial neurodegenerative phenotype” (MGnD).99,100”

In the citing paper

“Studies using an AD mouse model along with postmortem analyses of human AD brain tissue indicate that activation of the TREM2‐APOE pathway triggers transition in microglia from a homeostatic phenotype to a disease‐associated microglia (DAM) phenotype characterized by an increased inflammatory response. 123”

In the citing paper

“recent transcriptomic studies of microglia in normal and Aβ-mice identified subpopulations defined as disease-associated microglia (DAM)8,24.”

In the citing paper

“Physiological housekeeping functions include synaptic remodeling (a function critical for CNS development, homeostasis, and neurodegeneration20–22), migration to sites of neuronal death to phagocytose dead or dying cells23,24 or debris, and maintaining myelin homeostasis25.”

In the citing paper

“the microglial response to amyloid plaques and/or tau pathology is increasingly thought to cause or contribute heavily to disease-related neurodegeneration [10], [11], [12], [13].”

In the citing paper

“Most microglia were primarily separated into three cluster groups characterised by different sets of transcription factors: clusters expressing homoeostatic genes (Clusters 0, 1 and 3), inflammatory cytokines (Clusters 2, 4, 5 and 7), or DAM-related genes (Clusters 6 and 8)5,7 (Fig. 3d, e, Supplementary Fig. 5a–f).”

In the citing paper

“These observations suggest that meningeal lymphatic ablation leads to a loss of homeostatic microglia, and acquisition of the DAM signature (and/or the neurodegenerative microglial signature)21,22,26, all of which is counteracted by passive immunotherapy.”

In the citing paper

“apoE signaling in microglia following phagocytosis of apoptotic neurons or in response to Aβ accumulation leads to a transcriptional switch from promoting homeostasis to promoting inflammation and neurodegeneration [150, 151].”

In the citing paper

“Thus, microglia surrounding plaques are a major source of plaque-associated ApoE, supporting recent findings30,31.”

In the citing paper

“sialoadhesin (SIGLEC1; also known as CD169) is a marker for mature dendritic cells and macrophages in both mice and humans48 and has been proposed as a marker for invading monocyte-derived macrophages in the CNS as it is not expressed in microglia in health or disease49–52.”

In the citing paper

“this method of distinguishing between cell types relies on relative surface marker expression as assessed by flow cytometry, which can have some limitations. For example, CD45 surface expression is known to be upregulated on microglia associated with amyloid-β (Aβ) plaques in the APP/PS1 mouse model of Alzheimer disease (AD)52.”

In the citing paper

“the absence of TGFβ1, a factor known to be required for the in vitro development of the molecular signature characteristic of adult microglia, in the CNS results in a paralytic neurologic disease in mice25.”

In the citing paper

“The upregulated genes in Aβ-plaque-associated microglia, also known as disease-associated microglia (‘DAM microglia’), included Axl, Apoe, Clec7a, Itgax, Lgals3 and Cst7”

In the citing paper

“Although it is clear that the DAM microglia identified in these studies are associated with Aβ plaques, it is not clear whether they have a protective or disease-inducing function (FIG. 2b).”

In the citing paper

“Transcriptomic analysis of microglia in an AD mouse model and in human AD has revealed a proinflammatory signature present in Aβ-plaque-associated microglia52,111,139,140 (FIG. 2a).”

In the citing paper

“In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, microglia have a transcriptional phenotype that is similar to that observed in ALS and AD models (see below)52.”

In the citing paper

“This phenotype was not observed in microglia in non-plaque areas, suggesting that the neuroinflammation associated with AD predominantly occurs in plaque-associated microglia.”

In the citing paper

“Moreover, suppression of microglial Cx3cr1 expression is associated with disease progression in EAE52.”

In the citing paper

“ApoE also suppresses the expression of major transcription factors of homeostatic microglia52.”

In the citing paper

“At the same time, there was an increase in the expression of genes encoding transcription factors such as class E basic helix-loop-helix protein 40 (Bhlhe40), transcription factor EC (Tfec), protein C-ets-2 (Ets2) and cAMP-dependent transcription factor ATF3 (Atf3).”

In the citing paper

“Phagocytosis of apoptotic neurons that were injected into the brain of naive mice suppressed the microglial homeostatic signature and resulted in a transcriptional profile that mimicked the molecular signature of MGnD microglia.”

In the citing paper

“In disease, several core homeostatic disease genes were suppressed, including those encoding the transcriptional regulators Mef2a, Mafb, Sall1 and early growth response protein 1 (Egr1).”

In the citing paper

“Across disease models, the induction of genes related to ApoE signalling and the suppression of TGFβ signalling in microglia were associated with neurodegeneration, resulting in a phenotype that was termed ‘MGnD’ (microglia neurodegenerative phenotype).”

In the citing paper

“This microglial phenotype switch was shown to be regulated by activation of TREM2-ApoE signalling via phosphatidylserine exposed on the apoptotic neurons52.”

In the citing paper

“Although it is not entirely clear how TREM2 regulates microglial signature phenotypes, TREM2 is known to recognize phosphatidylserine on the surface of apoptotic or damaged cells and to initiate ApoE signalling52.”

In the citing paper

“Moreover, genetic ablation of Apoe in MGnD microglia restored their homeostatic properties in a cell-autonomous fashion.”

In the citing paper

“Genetic targeting of Trem2 suppressed the ApoE pathway and restored homeostatic microglia in both AD and SOD1 mice52.”

In the citing paper

“Consistent with this, in MGnD microglia from Apoe−/− mice, miR-155 expression was suppressed52.”

In the citing paper

“Microglial expression of Axl is upregulated and Mer is downregulated in microglia exhibiting the MGnD phenotype52.”

In the citing paper

“Trem2, a myeloid protein involved in microglial survival and proliferation, regulates a checkpoint necessary for DAM and deletion of Trem2 prevents microglial accumulation around Aβ plaques and leads to additional neuritic damage [6, 14–17].”

In the citing paper

“Trem2, a myeloid protein involved in microglial survival and proliferation, regulates a checkpoint necessary for DAM and deletion of Trem2 prevents microglial accumulation around Aβ plaques and leads to additional neuritic damage [6, 14–17].”

In the citing paper

“In the anti-inflammatory/phagocytic DAM module, Apoe was identified as a hub gene strongly associated with AD risk. This agrees with other lines of evidence confirming the role of Apoe in regulating DAM responses and Aβ-clearance in AD [16, 21].”

In the citing paper

“The top enrichment term in this group is “Microglia genes upregulated in neurodegenerative diseases” (p = 2.79E-09; Krasemann et al., 2017).”

In the citing paper

“Since deletion of Trem2 in mice blocks the proper transcriptional activation of microglia in neurodegenerative diseases (Keren-Shaul et al., 2017; Krasemann et al., 2017; Wang et al., 2015), it is difficult to predict a priori whether TREM2 gene dosage increase could broadly or subtly alter the microglial transcriptome response, and what impact it would exert on the disease process.”

In the citing paper

“Prior studies (e.g. Keren-Shaul et al., 2017; Krasemann et al., 2017) and our current one (Figure S1A–S1B) showed elevated Trem2 expression occurs at relatively late disease stages.”

In the citing paper

“P7-C1 microglia exhibited characteristic expression of many genes that have recently been shown to be up-regulated in degenerative disease-associated microglia (DAM)”

In the citing paper

“We discovered a proliferative region-associated microglia (PAM) subset, mainly found in developing white matter, that share a characteristic gene signature with degenerative disease-associated microglia (DAM).”

In the citing paper

“unlike DAM (Keren-Shaul et al., 2017; Krasemann et al., 2017), appearance of PAM did not depend on a TREM2-APOE axis”

In the citing paper

“Particularly, we identified a subset of microglia, named proliferative region-associated microglia (PAM), that mimicked gene expression pattern of degenerative disease-associated microglia (DAM) (Keren-Shaul et al., 2017; Krasemann et al., 2017).”

In the citing paper

“It has been shown that transcriptional changes in degenerative disease-associated microglia depend on the TREM2-APOE pathway, and the DAM signature genes such as Spp1, Gpnmb and Clec7a are suppressed in disease models that also lack Trem2 or Apoe (Keren-Shaul et al., 2017; Krasemann et al., 2017).”

In the citing paper

“Indeed, while early postnatal PAM engulf newly formed oligodendrocytes and possibly newborn astrocytes during development, DAM are also phagocytic and involved in phagocytosis of Aβ plaques in AD models (Keren-Shaul et al., 2017; Krasemann et al., 2017).”

In the citing paper

“DAM or MGnD are found in neurodegenerative disorders including AD, amyotrophic lateral sclerosis (ALS) and multiple sclerosis [41, 45].”

In the citing paper

“Customized NanoString-based gene expression analysis, which uses molecular barcodes and microscopic imaging to detect and count unique transcripts in hybridization reactions, revealed APOE and TGFβ as the major upstream regulators of MGnD microglia.”

In the citing paper

“Upregulation of APOE suppresses gene expression of microglial homeostatic transcriptional factors including Spi1, Mef2a, Mafb, Smad3”

In the citing paper

“and induces inflammatory response via induction of transcription factors Bhlhe40, Tfec, Atf, and inflammatory miRNA miR-155”

In the citing paper

“Krasemann et al. found dystrophic neurites stimulate TREM2 –APOE pathway that results in phenotypic switch from homeostatic to MGnD microglia [45].”

In the citing paper

“In diseased states, microglia can become dysfunctional and neurotoxic, which are referred as disease-associated microglia (DAM) or microglia neurodegenerative phenotypes (MGnD).”

In the citing paper

“which if genetically ablated, can reverse abnormal microglia signature and ameliorate disease in SOD1 mice, a mouse model for ALS [12, 45].”

In the citing paper

“cbMg in the adult mouse brain show a primed/phagocytic microglia phenotype11–13 characterized by a less ramified morphology, reduced branching sites (Supplementary Fig. 1a), decreased cell volume (Supplementary Fig. 1b,c), and an increase in CD68+ lysosome content (Fig. 1a, Supplementary Fig. 1b,c).”

In the citing paper

“Furthermore, cbMg show an increase in the expression of genes characteristic of immature microglia9,10, as well as genes that are expressed in neurodegenerative disease-associated microglia (such as primed microglia, MGnD, and DAMs)11–13 (Supplementary Fig. 5c,d, Supplementary Table 4).”

In the citing paper

“The cerebellar microglia phenotype is reminiscent of microglia during early brain development9,10 as well as microglia associated with neurodegenerative disease11–13.”

In the citing paper

“The increase in clearance-associated genes and the reduction in surveillance-related genes in PRC2-deficient stMg are reminiscent of transcriptional changes observed in microglia during neurodegenerative disease11–13 (Supplementary Fig. 11h).”

In the citing paper

“This is another key characteristic feature of early microglia progenitors9,10 as well as microglia exposed to dying neurons during different diseases11–13.”

In the citing paper

“We found that the cbMg-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration11–13 and early brain development9,10, two stages of life characterized by enhanced neuronal attrition and heightened microglia clearance activity.”

In the citing paper

“In particular, a significant fraction of the cbMg-expressed genes have been implicated in the detection, engulfment, and catabolism of debris both in peripheral macrophages carrying out cell clearance21 as well as in microglia associated with ageing and neurodegeneration11–13.”

In the citing paper

“While PRC2-deficient stMg and cxMg show no up-regulation of complement or pro-inflammatory genes generally associated with microglia activation during neurodegeneration11–13,34, it is still plausible that their aberrant clearance activity may lead to the enhanced engulfment of C1q/C3-tagged spines, the presence of which increases with age44.”

In the citing paper

“The end-stage activated microglia appear to display a conserved core-expression profile harbouring certain degrees of diversity across individual disease phenotypes27,28.”

In the citing paper

“This signature is characterized by a suppression of microglial homeostatic genes, and an induction of pro-inflammatory genes as well as genes involved in microglial phagocytotic function targeting degenerated/injured neurons and amyloid plaques27,28.”

In the citing paper

“the expression of Apoe — the hallmark gene of the MGnD phenotype that has been found to be upregulated in microglia in all currently-assessed neurodegenerative diseases — is suppressed in M1 microglia.”

In the citing paper

“The MGnD phenotype can largely be recapitulated by injecting apoptotic neurons into mouse brain parenchyma, where the subset of microglia that are activated to phagocytose apoptotic neurons show a similar molecular phenotype to the MGnD phenotype28.”

In the citing paper

“TREM2−/− amyloid-β depositing mice consistently show downregulation of inflammatory genes, such as Tnf and Il1b45–47, and also of key genes associated with the MGnD phenotype, such as c-type lectin domain family 7 member A (Clec7a) and integrin subunit alpha X (Itgax)27,28”

In the citing paper

“Interestingly, TREM2 shares the same pathways with ApoE in regulating the microglial neurodegenerative phenotype.”

In the citing paper

“TREM2 deletion in APPPS1–21 [G] or superoxide dismutase 1 (SOD1) mice [G] results in ApoE downregulation and a similar suppression of core inflammatory MGnD genes and restoration of homeostatic genes28.”

In the citing paper

“Targeting TREM2 signaling in the facial nerve axotomy model ameliorates neuronal loss28, and ablation of TREM2 in tauopathy mice attenuates neuroinflammation and neurodegeneration67, similar to the effect of ApoE deletion.”

In the citing paper

“ApoE deletion prevents full acquisition of the microglial neurodegenerative phenotype with suppression of key MGnD genes28”

In the citing paper

“Contrary to LPS treatment where ApoE deletion amplifies the immune response, under neurodegenerative or neuroinflammatory conditions, ApoE deficiency attenuates inflammation28,69,97,107 and disease severity69,106,107.”

In the citing paper

“emerging evidence suggests that APOE, a potent immune modulator and strongest of genetic risk factors for LOAD [113–115], may regulate neurodegeneration in a TREM2-mediated fashion [116, 117].”

In the citing paper

“Itgax/CD11C is an integrin or cell surface antigen, and is up-regulated in a number of recent RNA-seq studies in response to amyloid plaques (58,59,61,84).”

In the citing paper

“Recent important studies have also shown that impaired/absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage (37,61,84–87,95–99).”

In the citing paper

“Indeed, a series of recent studies identified transcriptional signatures in response to AD-associated pathology, neurodegeneration and apoptotic neurons, which were in part dependent on Trem2 and included Igf1, Csf1, Itgax, Clec7a and Arg1, at least in mice (58,59,61,84,86).”

In the citing paper

“Interestingly, when we tested expression of genes that show substantial changes in transgenic mice associated with AD (43,44) a number of aspects of gene expression were mimicked by anti-inflammatory IL-4 stimulation, particularly the increased expression of genes associated with the neurodegenerative signature, including Igf1, Itgax, Clec7a and Arg1 (58,59,61,84,86).”

In the citing paper

“The downregulation of genes associated with microglial homeostasis, Tmem119, P2ry12, and Cx3cr1, have been identified in many murine models representing AD [44,77–80], amyotrophic lateral sclerosis (ALS) [44,77,79], and multiple sclerosis [79]; suggesting similar signaling pathways are present.”

In the citing paper

“Intriguingly, P2ry13 and Gpr34, mouse orthologs of genes we identified in our human microglial gene set, are known to show down-regulation in so-called DAM (86–88) that are found in AD and other neurological disorders.”

In the citing paper

“Another critical issue for future work will be to determine the mechanisms responsible for sexually dimorphic microglial gene expression profiles reported in mice (28, 88) and to what extent they apply to human microglia.”