Profiling Microglia From Alzheimer’s Disease Donors and Non-demented Elderly in Acute Human Postmortem Cortical Tissue

Alsema, Astrid M.; Jiang, Qiong; Kracht, Laura; Gerrits, Emma; Dubbelaar, Marissa L.; Miedema, Anneke; Brouwer, Nieske; Hol, Elly M.; Middeldorp, Jinte; Dijk, Roland van; Woodbury, Maya E.; Wachter, Astrid; Xi, Simon; Möller, Thomas; Biber, Knut; Kooistra, Susanne M.; Boddeke, Erik; Eggen, Bart J. L.

doi:10.3389/fnmol.2020.00134

Cited by 63 publications

(68 citation statements)

References 52 publications

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“…TREM2 upregulation had also been determined in peripheral mononuclear cells from AD patients and mild cognitive impairment [52,53], implicating that the TREM2 upregulation may be a systemic response of myeloid cells with the progression of AD. The snRNAseq data on individual AD postmortem sample and AD mouse model also revealed that TREM2/Trem2 was upregulated in AD pathology and AD-related conditions ( Figure 1D,E) [45,[54][55][56][57]. In addition, Trem2 is also upregulated in an amyloidosis progression-related pattern, predominantly in plaquesurrounding microglia [58].…”

Section: Trem2 and Disease-associated Microglia (Dam)mentioning

confidence: 80%

“…In addition, such disparities may also remind us to pay attention to the dose effect of Trem2 as well as the interaction of Trem2 with other inflammatory pathways. Noteworthy, it should be mindful that mouse models may not comprehensively recapitulate microglial changes in AD patients based on the inconsistent microglial transcriptomics profiling between AD mouse models and AD [54,56,81,82]. Therefore, further patients-based studies may help to determine the roles of TREM2 in shaping microglial phenotypes and DAM functions in AD.…”

Section: Ank Hif1a Tgfb1mentioning

confidence: 99%

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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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Section: Trem2 and Disease-associated Microglia (Dam)mentioning

confidence: 80%

Section: Ank Hif1a Tgfb1mentioning

confidence: 99%

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

Xue

2021

Cells

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“…Given the difficulty in capturing microglia and endothelial cells using snRNA-seq [ 54 ], additional transcriptomic investigations of these cells in the white matter of CTE are warranted, especially in light of previous studies showing increases in neuroinflammatory microglia in DLF cortex in CTE [ 11 – 13 ]. Future studies isolating microglia, neurons, and endothelial cells for in depth transcript profiling are also warranted [ 3 , 51 ]. Furthermore, additional studies specifically isolating astrocyte nuclei for sequencing will enhance the findings presented here [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Chancellor

Duke-Cohan

et al. 2021

Acta Neuropathol

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Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts. White matter rarefaction and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. In astrocytes, total cell numbers were indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and suggest that white matter alterations are a critical aspect of CTE neurodegeneration.

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“…Compared with astrocytes, the APOE expression in microglia is upregulated in AD patients (Mathys et al, 2019). The upregulation of APOE in microglia can result from either a disrupted regulation specifically in microglia or a disease-associated subpopulation, although recent studies have not detected an AD-specific subpopulation in microglia in the cortex of AD patients (Alsema et al, 2020;Mathys et al, 2019). More studies are needed to examine this regulatory effect of the APOE ε4 variant at the cell level, including microglia.…”

Section: Discussionmentioning

confidence: 99%

Allele-specific analysis reveals exon- and cell-type-specific regulatory effects of Alzheimer’s disease-associated genetic variants

Loika

Kulminski

2021

Preprint

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Elucidating regulatory effects of Alzheimer's disease (AD)-associated genetic variants is critical for unraveling their causal pathways and understanding the pathology. However, their cell-type-specific regulatory mechanisms in the brain remain largely unclear. Here, we conducted an analysis of allele-specific expression quantitative trait loci (aseQTLs) for 33 AD-associated variants in four brain regions and seven cell types using ~3000 bulk RNA-seq samples and >0.25 million single nuclei. We develop a flexible framework using a hierarchical Poisson mixed model unifying samples in both allelic and genotype-level expression data. We identified 24 AD-associated variants (~73%) that are allele-specific eQTLs (aseQTLs) in at least one brain region. Multiple aseQTLs are region-dependent or exon-specific, such as rs2093760 with CR1, rs7982 with CLU, and rs3865444 with CD33. Notably, the APOE e4 variant reduces APOE expression across all regions, even in healthy controls. In pinpointing the cell types responsible for the observed region-level aseQTLs, we found rs2093760 as an aseQTL of CR1 in oligodendrocytes but not in microglia. Many AD-associated variants are aseQTLs in microglia or monocytes of immune-related genes, including HLA-DQB1, HLA-DQA2, CD33, FCER1G, MS4A6A, SPI1, and BIN1, highlighting the regulatory role of AD-associated variants in the immune response. These findings provide further insights into potential causal pathways and cell types mediating the effects of the AD-associated variants.

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Profiling Microglia From Alzheimer’s Disease Donors and Non-demented Elderly in Acute Human Postmortem Cortical Tissue

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Cited by 63 publications

References 52 publications

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

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

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Allele-specific analysis reveals exon- and cell-type-specific regulatory effects of Alzheimer’s disease-associated genetic variants

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