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

The disease-associated microglia response depends on TREM2 and APOE in mouse models of Alzheimer's disease and metabolic disease.

“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).”

APOE can bind with the intracellular domain of TREM2 and switch microglia from a homeostatic phenotype to a neurodegenerative phenotype in multiple neurodegenerative models including AD, indicating the APOE-TREM2 pathway as proinflammatory signaling.

“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”

Microglial accumulation at plaques and plaque-driven morphological and transcriptional responses depend on microglial surface receptor-mediated signalling, which involves activation of the tyrosine kinase SYK and one of its key downstream targets PLCγ2.

“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.”

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.

“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).”

These pathways highlight how neuronal and glial interactions modulate microglial activity through Apoe, App, Trem2, and Lrp1.

“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].”

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).”

The TREM2/TYROBP pathway regulates the switch from a homeostatic to a neurodegenerative molecular signature by inducing miR155 via apolipoprotein E (APOE) signaling.

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

DAM/MGnD phenotype has a protective role, with TREM2-dependent functions required initially to prevent plaque seeding and later enhancing consolidation of Aβ into compact aggregates.

“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.”

AD patients with TREM2 mutations display less compact Aβ plaques, fewer plaque-associated microglia, enhanced tau pathology and neuritic plaques.

“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]”

Single-cell RNA sequencing identified gene signatures characteristic of protective and dysfunctional microglial subpopulations in AD.

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

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.

“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.”

Existing categories such as DAM and MGnD do not fully explain how protective immune regulation is achieved within the Alzheimer's brain.

“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.”

The phenotype of microglia 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.

“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].”

CD11c+ microglia are known to increase in chronic inflammatory and neurodegenerative conditions as well as during development.

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

Our findings in humans were validated in mice with inactivated Plcg2 expression, which reduced expression levels of AD-associated microglial genes including CLEC7A, C3, and PIK3R5, in comparison with WT mice.

“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.”

The existence of DAM in mice and humans has recently been confirmed in tauopathy AD models, aging, and other neurodegenerative diseases such as ALS and multiple sclerosis.

“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).”

Ligation of the Trem2 receptor by ApoE is sufficient to promote phagocytosis in TREM2-expressing microglial cells and activates Apoe RNA expression.

“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”

High-confidence Trem2+ monocytes were identified by expression of known TREM2+ monocyte markers (TREM2, APOE, CSF1R) using gene-weighted density estimation in Nebulosa.

“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”

The in vivo model based on intraperitoneal injection of LPS induces a well-defined microglial proinflammatory phenotype that is different from the molecular signature of disease-associated microglia.

“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).”

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.

“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).”

Microglial TET2 is upregulated in vivo in two well-defined models of microglia polarization: a neuroinflammatory mouse model induced by repeated intraperitoneal injections of LPS, and AD, including human patients and transgenic mice (5xFAD).

“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).”

Twenty-one core genes associated with the XO4+/XO4− phenotype were identified as altered in several studies of neurodegenerative disease-associated microglia (DAM).

“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”

The XO4+-associated gene expression signature identified here partially overlaps with other microglia signatures obtained from aged, APP/PS1, 5xFAD or tau model mice.

“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”

Recent studies identified a novel microglial phenotype near Aβ plaques that was dependent on Trem2 and Apoe in two mouse models of AD.

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

Plaque-adjacent microglia in human post mortem AD brains upregulate LPL and downregulate P2RY12.

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

ARMs induce Apoe expression up to 27-fold compared to homeostatic microglia.

“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.”

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.

“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 5xFAD compared to WT mice, DAM genes (Cst7, Apoe, Ctsb, Ctsd, Ctss, Psen1) are upregulated and homeostatic genes (P2ry12, Tmem119, Csf1r) are downregulated.

“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].”

Together with TREM2, APOE regulates microglial response to Aβ plaques and neurofibrillary tangles in AD and other neurodegenerative diseases.

“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.”

ApoE reduction or depletion attenuates neuroinflammation and alleviates pathological changes in various mouse models of amyloid and tau pathology.

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

Carriage of the APOE4 allele is associated with increased neuroinflammation and metabolic disturbances within neurons and glial cells.

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

TG-Abi3-Gngt2−/− mice showed upregulated MGnD gene profile signature (p < 0.05 relative to TG-Abi3-Gngt2+/−).

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

The analysis revealed 5 discrete microglial clusters, each representing a different microglial state, including previously characterized homeostatic, transitioning, activated plaque-responsive (Act), and IFN-responsive microglial subsets.

“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).”

Shared DEGs between Clec7a+ plaque-associated microglia from APP/PS1 vs WT and APP/PS1:miR-155 cKO vs APP/PS1 microglia were associated with enhanced IFN signaling.

“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 case-control frameworks, reanalysis of two examples from the literature demonstrates that without knowledge of the exAM signature, it can result in spurious identification of the exAM signature as differentially expressed.

“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.”

The opposing protective and harmful microglial states are accompanied by broad changes in gene expression, suggesting that defined transcriptional programs in microglia may govern their neuroprotective or neurotoxic functions.

“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.”

TREM2 is influential in driving microglial acquisition of the DAM transcriptome.

“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).”

Several subsets of microglia with unique molecular and functional phenotypes exist in the healthy, aged, and degenerating brain.

“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.”

Numerous studies targeting members of the TREM2/TYROBP pathway (Trem2, Tyrobp, and miR155) support beneficial outcomes associated with maintenance and/or restoration of homeostatic functions of microglia.

“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”

P2RY12 is considered a homeostatic microglia marker because of its downregulation in neurodegenerative and neuroinflammatory models, including amyotrophic lateral sclerosis, AD and MS.

“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).”

Recent transcriptomic studies identified a subset of microglia with unique signatures termed DAM or MGnD during neurodegeneration.

“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 mice with cerebral amyloidosis, TREM2 ablation abrogated MGnD phenotype and reduced microglial response to plaques.

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

Mechanistic studies of the TREM2-APOE pathway showed that microglial phenotypes in neurodegeneration are actively regulated transcriptional programs, not passive responses to tissue damage.

“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].”

A neurodegenerative disease-associated microglial signature has been described, termed MGnD.

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

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

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

MGnD represents an induced inflammatory signature mediated by the TREM2-APOE pathway, which suppresses the M0 signature.

“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.”

Trem2 is present in Signatures A and C.

“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.”

Recent findings point to microglia heterogeneity in neurodegeneration.

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

The transcriptional shift microglia undergo in response to Aβ is thought to be at least partially dependent on TREM2 expression.

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

A critical role for transcriptional changes in microglial activation has been highlighted, and unique RNA signatures are used to identify distinct microglial subpopulations.

“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 central nervous system, APOE is upregulated in MGnD.

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

Neurodegenerative microglia (MGnD), also referred to as disease-associated microglia, are regulated by reciprocal suppression of TGFβ and induction of APOE signaling in different neurodegenerative models, including AD.

“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 .”

Additional characterization of microglia by analyzing the acute response to neurodegeneration via intracranial injection of apoptotic neurons showed upregulation of antigen presentation- and IFNγ signaling-related genes in Itgb8-cKO mice compared to control mice.

“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).”

Beyond type I IFNs, cGAS activation alone triggers a core microglial gene expression program shared between many neurodegenerative disease states and during ageing.

“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.”

The potential involvement of TET2 in disease-associated microglia 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.

“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.”

2031 (72.3%) of 2810 genes associated with XO4+ microglia were not reported in previous RNA-sequencing studies of microglia in neurodegeneration.

“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”

APOE is involved in the regulation of DAMs and the microglial response to amyloid.

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

The DAM (DAM/MGnD) signature is dependent on the TREM2-APOE pathway.

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

E3S/S did not affect disease-associated microglial signatures (DAMs) or microglial neurodegenerative phenotype (MGnD).

“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.”

E3S/S reduced cGAS-STING-IFN signaling in microglia.

“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.”

APOE expression is markedly upregulated by reactive microglia in the brains of individuals with AD.

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

This upregulation is a key element of a conserved transcriptional signature of reactive microglia found in multiple neurodegenerative diseases.

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

Microglia-derived apoE cell-autonomously promotes microglial activation towards the neurodegenerative MGnD/DAM phenotype.

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

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

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

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

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

In AD mouse models, a subset of microglia exhibits a neurodegenerative/disease-associated phenotype characterized by upregulation of pro-inflammatory genes.

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

Microglia can significantly upregulate APOE expression as part of their DAM response to amyloid plaques.

“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).”

The DAM response is dependent on APOE expression but it was thought that APOE expression in microglia was essential.

“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.”

These genes are reported to be associated with pathologic signatures in AD, most notably DAM and MGnD and PIG.

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

Cathepsin B signal appears punctate when localized to lysosomes, whereas it becomes diffuse when localized to the cytosol upon LMP.

“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.”

Cathepsin B leaking from destabilized lysosomes may mediate NLRP3 inflammasome activation upon SHIP1 inhibition.

“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.”

The intracellular signaling pathway downstream of TREM2 is complex and involves many molecules in addition to PLCG2, including Syk and PI3K.

“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”

TREM2 is one of the key receptors modulating PLCγ2 activity.

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

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.

“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].”

Validation data for all commercial antibodies are available on the manufacturer's website, including previously published papers.

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

Ptgs2 and Cybb are the two highest induced genes upon repeated systemic LPS injections, based on publicly available data.

“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 different single cell RNAseq of microglia in different AD models, the expression of TET2 was found not to be upregulated.

“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).”

Hif1a is not a signature gene described by Krasemann et al.

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

These controversial outcomes highlight a complex dual role of microglia, also observed in other brain diseases, and might be attributed to total removal of microglia being harmful, whereas targeting specific microglia activation states later in disease might prolong survival time.

“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.”

The loss of the homeostatic signature is especially severe in prion diseases compared to other neurodegenerative conditions.

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

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 reciprocal regulation of both proteins in prion disease.

“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].”

A disease-specific microglia signature that is commonly dysregulated in brain diseases including AD has been identified.

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

Disease-associated microglia have a transcriptional signature distinct from homeostatic microglia, which declines in mouse Alzheimer's disease models.

“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.”

The microglial gene changes were highly concordant between the 7-month and 15-month datasets and with previously published single-cell RNA-seq of sorted microglia.

“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.”

The human microglial signature in Alzheimer's disease is distinct from mouse disease-associated microglia, resembles the peripheral nerve injury phenotype, and may be partly instructed by IRF8.

“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 mice accumulating amyloid beta, microglia replace their homeostatic signature with a disease-associated microglia signature that is partially Trem2-dependent.

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

Several genetically distinct subtypes of microglia have been discovered, namely homeostatic microglia and 'disease-associated microglia' (DAM) or 'microglial neurodegenerative phenotype' (MGnD).

“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”

Activation of TREM2-APOE pathway triggers transition in microglia from homeostatic phenotype to disease-associated microglia (DAM) phenotype characterized by increased inflammatory response.

“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”

Transcriptomic studies identified disease-associated microglia (DAM) subpopulations in normal and Aβ-mice.

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

Housekeeping functions include synaptic remodeling, migration to sites of neuronal death for phagocytosis, and maintenance of myelin homeostasis.

“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.”

The microglial response to amyloid plaques and/or tau pathology is increasingly thought to cause or contribute heavily to disease-related neurodegeneration.

“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].”

Most microglia are primarily separated into three cluster groups characterised by homoeostatic genes, inflammatory cytokines, or DAM-related genes.

“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).”

Meningeal lymphatic ablation causes loss of homeostatic microglia and acquisition of a disease-associated microglial signature, effects that passive immunotherapy counteracts.

“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.”

ApoE signaling in microglia following phagocytosis of apoptotic neurons or in response to amyloid-β accumulation leads to a transcriptional switch from promoting homeostasis to promoting inflammation and neurodegeneration.

“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].”

Microglia surrounding plaques are a major source of plaque-associated ApoE.

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

SIGLEC1/CD169 is not expressed in microglia in health or disease and has been proposed as a marker for invading monocyte-derived macrophages in the CNS.

“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.”

Distinguishing cell types by relative surface marker expression using flow cytometry has limitations, and CD45 is upregulated on microglia associated with Aβ plaques in the APP/PS1 AD mouse model.

“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.”

Absence of TGFβ1 in the CNS causes a paralytic neurologic disease in mice, and TGFβ1 signalling is inhibited in microglia associated with neurodegeneration where the homeostatic signature is suppressed.

“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.”

Upregulated genes in Aβ-plaque-associated microglia, called disease-associated microglia or DAM microglia, include Axl, Apoe, Clec7a, Itgax, Lgals3 and Cst7.

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

The DAM microglia identified in these studies are associated with Aβ plaques.

“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).”

Transcriptomic studies of microglia in an Alzheimer disease mouse model and in human Alzheimer disease found a proinflammatory signature in microglia associated with Aβ plaques.

“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 EAE mouse model of multiple sclerosis, microglia have a transcriptional phenotype similar to that seen in ALS and Alzheimer disease models.

“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.”

The proinflammatory phenotype was not seen in microglia located outside plaque areas.

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

Suppression of microglial Cx3cr1 expression is associated with disease progression in EAE.

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

ApoE suppresses expression of major transcription factors of homeostatic microglia.

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

In disease, expression of transcription factors Bhlhe40, Tfec, Ets2 and Atf3 increases.

“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).”

Phagocytosis of apoptotic neurons injected into naive mouse brain suppressed the microglial homeostatic signature and produced a transcriptional profile mimicking MGnD microglia.

“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 disease, several core homeostatic genes are suppressed, including Mef2a, Mafb, Sall1 and Egr1.

“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).”

Across disease models, induction of ApoE signalling genes and suppression of TGFβ signalling in microglia are associated with neurodegeneration, producing the MGnD phenotype.

“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).”

This microglial phenotype switch is regulated by activation of TREM2-ApoE signalling via phosphatidylserine exposed on apoptotic neurons.

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

TREM2 recognizes phosphatidylserine on apoptotic or damaged cells and initiates ApoE signalling.

“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.”

Genetic ablation of Apoe in MGnD microglia restored their homeostatic properties in a cell-autonomous fashion.

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

Genetic targeting of Trem2 suppressed the ApoE pathway and restored homeostatic microglia in both Alzheimer disease and SOD1 mice.

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

In MGnD microglia from Apoe−/− mice, miR-155 expression is suppressed.

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

Microglial expression of Axl is upregulated and Mer is downregulated in MGnD microglia.

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

Deletion of Trem2 prevents microglial accumulation around amyloid β plaques and leads to additional neuritic damage.

“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].”

Trem2 regulates a checkpoint necessary for DAM.

“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].”

Apoe regulates DAM responses and Aβ-clearance in AD.

“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].”

TD2 genes are enriched for microglia genes upregulated in neurodegenerative diseases.

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

Deletion of Trem2 in mice blocks proper transcriptional activation of microglia in neurodegenerative diseases.

“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.”

Elevated Trem2 expression occurs at relatively late disease stages.

“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.”

P7-C1 microglia express many DAM-associated genes and down-regulate homeostatic genes.

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

A subset of proliferative region-associated microglia (PAM) exists mainly in developing white matter and shares a gene signature with degenerative disease-associated microglia (DAM).

“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).”

Appearance of PAM does not depend on a TREM2-APOE axis.

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

A subset of early postnatal microglia, named proliferative region-associated microglia (PAM), mimics the gene expression pattern of disease-associated microglia (DAM).

“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 degenerative disease models, microglial transcriptional changes and DAM signature genes (Spp1, Gpnmb, Clec7a) depend on the TREM2-APOE pathway and are suppressed when Trem2 or Apoe is absent.

“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).”

DAM are phagocytic and involved in phagocytosis of Aβ plaques in AD models.

“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).”

DAM or MGnD are found in neurodegenerative disorders including AD, ALS, and multiple sclerosis.

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

NanoString-based gene expression analysis revealed APOE and TGFβ as major upstream regulators of MGnD microglia.

“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.”

APOE upregulation suppresses expression of homeostatic microglial transcription factors Spi1, Mef2a, Mafb, and Smad3.

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

APOE upregulation induces inflammatory response via Bhlhe40, Tfec, Atf, and miR-155.

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

Krasemann et al. found that dystrophic neurites stimulate the TREM2-APOE pathway, resulting in a phenotypic switch from homeostatic to MGnD microglia.

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

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

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

Genetic ablation of miR-155 can reverse abnormal microglia signature and ameliorate disease in SOD1 ALS mice.

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

Adult mouse cerebellar microglia show a primed/phagocytic phenotype characterized by less ramified morphology, reduced branching sites, decreased cell volume, and increased CD68+ lysosome content.

“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).”

Cerebellar microglia show increased expression of genes characteristic of immature microglia and genes expressed in neurodegenerative disease-associated microglia.

“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).”

The cerebellar microglia phenotype resembles microglia during early brain development and microglia associated with neurodegenerative disease.

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

The increase in clearance-associated genes and reduction in surveillance-related genes in PRC2-deficient striatal microglia are reminiscent of transcriptional changes observed in microglia during neurodegenerative disease.

“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).”

This reduction in homeostatic microglia genes is another key characteristic feature of early microglia progenitors and microglia exposed to dying neurons during different diseases.

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

The cerebellar microglia-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration and early brain development.

“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.”

A significant fraction of cerebellar microglia-expressed genes have been implicated in detection, engulfment, and catabolism of debris in peripheral macrophages carrying out cell clearance and in microglia associated with ageing and neurodegeneration.

“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 PRC2-deficient stMg and cxMg, complement and pro-inflammatory genes typically linked to microglial activation in neurodegeneration are not increased.

“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.”

End-stage activated microglia display a conserved core-expression profile harbouring certain degrees of diversity across individual disease phenotypes.

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

The common disease-associated microglial cell signature, defined as the MGnD or DAM phenotype, is characterized by suppression of microglial homeostatic genes and induction of pro-inflammatory genes as well as genes involved in microglial phagocytotic function targeting degenerated/injured neurons and amyloid plaques.

“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.”

The expression of Apoe, the hallmark gene of the MGnD phenotype that is upregulated in microglia in all currently-assessed neurodegenerative diseases, is suppressed in M1 microglia.

“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.”

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

“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.”

TREM2−/− amyloid-β depositing mice consistently show downregulation of inflammatory genes, such as Tnf and Il1b, and also of key genes associated with the MGnD phenotype, such as Clec7a and Itgax.

“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”

TREM2 shares the same pathways with ApoE in regulating the microglial neurodegenerative phenotype.

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

TREM2 deletion in APPPS1-21 or SOD1 mice results in ApoE downregulation and a similar suppression of core inflammatory MGnD genes and restoration of homeostatic genes.

“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.”

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

“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.”

ApoE deletion prevents full acquisition of the microglial neurodegenerative phenotype with suppression of key MGnD genes.

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

Under neurodegenerative or neuroinflammatory conditions, ApoE deficiency attenuates inflammation and disease severity.

“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.”

APOE may regulate neurodegeneration in a TREM2-mediated fashion.

“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].”

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.

“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).”

Impaired or absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage.

“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).”

Recent studies identified transcriptional signatures in response to AD-associated pathology, neurodegeneration and apoptotic neurons that were in part dependent on Trem2 and included Igf1, Csf1, Itgax, Clec7a and Arg1, at least in mice.

“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).”

When genes that show substantial changes in transgenic mice associated with AD were tested, a number of aspects of gene expression were mimicked by anti-inflammatory IL-4 stimulation, particularly increased expression of genes associated with the neurodegenerative signature, including Igf1, Itgax, Clec7a and Arg1.

“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).”

Downregulation of homeostatic genes Tmem119, P2ry12, and Cx3cr1 has been identified in many murine models representing AD, ALS, and multiple sclerosis, suggesting similar signaling pathways are present.

“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.”

P2ry13 and Gpr34, mouse orthologs of genes identified in our human microglial gene set, are known to show down-regulation in so-called DAM that are found in AD and other neurological disorders.

“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.”

Sexually dimorphic microglial gene expression profiles have been reported in mice.

“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.”