Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation

Srinivasan, Karpagam; Friedman, Brad A.; Etxeberría, Ainhoa; Huntley, Melanie A.; Brug, Marcel P. van der; Foreman, Oded; Paw, Jonathan S.; Modrušan, Zora; Beach, Thomas G.; Serrano, Geidy E.; Hansen, David V.

doi:10.1016/j.celrep.2020.107843

Cited by 264 publications

(283 citation statements)

References 48 publications

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“…Converging studies pointed out that Lyz2 was one of the commonly induced microglial genes by disease-associated microglia (DAM) and microglial neurodegenerative phenotype (MGnD), suggesting the microglial expression of Lyz2 played an important role in responding to Aβ stimulus in AD mouse models of amyloidosis ( 55 , 70 , 71 ). These findings argue that Lyz2 gene is mainly expressed in CNS myeloid cells rather than other CNS cells, which could be confirmed in the summarized RNA-seq data website “The Myeloid Landscape 2” ( 72 ). Purified CNS cell types showed both human Lyz and mouse ortholog Lyz2 only significantly expressed in CNS myeloid cells rather than other CNS cell types including neurons (GSE73721, GSE52564, GSE75431).…”

Section: Discussionsupporting

confidence: 59%

Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis

Hunt

Selenica

et al. 2021

Front. Immunol.

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Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aβ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.

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Section: Discussionsupporting

confidence: 59%

Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis

Hunt

Selenica

et al. 2021

Front. Immunol.

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“…(C) Trem2/TREM2 upregulations in multiple AD animal models and AD postmortem samples. Metadata were acquired from The Myeloid Landscape 2 [44]. (D) TREM2 upregulations in AD postmortem samples (p < 0.05).…”

Section: Introductionmentioning

confidence: 99%

TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

Xue

2021

Cells

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Alzheimer’s disease (AD) is a lethal neurodegenerative disorder primarily affecting the aged population. The etiopathogenesis of AD, especially that of the sporadic type, remains elusive. The triggering receptor expressed on myeloid cells 2 (TREM2), a member of TREM immunoglobulin superfamily, plays a critical role in microglial physiology. Missense mutations in human TREM2 are determined as genetic risk factors associated with the development of sporadic AD. However, the roles of TREM2 in the pathogenesis of AD are still to be established. In this review, we outlined the influence of Trem2 on balance of pro- and anti-inflammatory microglial activations from a perspective of AD mouse model transcriptomics. On this basis, we further speculated the roles of TREM2 in different stages of AD, which may shed light to the development of TREM2-targeted strategy for the prevention and treatment of this neurodegenerative disorder.

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“…Furthermore, human AD-microglia seem to be enriched in some of these DAM genes, such as APOE, CD74, HLA-DRB1, and show overlap in molecular pathways related to lipid and lysosomal biology. However, there is likely to be human-specific AD-microglia subpopulations since many gene signatures do not overlap between the mouse and human AD-associated microglia 41,42 . These observations suggest the role of TREM2 and DAMs in neurodegenerative diseases is context-and disease state-specific.…”

Section: Mainmentioning

confidence: 99%

AD-linked R47H-TREM2mutation induces disease-enhancing proinflammatory microglial states in mice and humans

Sayed

Kodama²,

Udeochu

et al. 2020

Preprint

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The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

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Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation

Cited by 264 publications

References 48 publications

Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis

Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis

TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

AD-linked R47H-TREM2mutation induces disease-enhancing proinflammatory microglial states in mice and humans

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