APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease

Nguyen, Aivi T.; Wang, Kui; Hu, Gang; Wang, Xuran; Miao, Zhen; Azevedo, Joshua A; Suh, EunRan; Deerlin, Vivianna M. Van; Choi, David; Roeder, Kathryn; Li, Mingyao; Lee, Edward B.

doi:10.1007/s00401-020-02200-3

Cited by 131 publications

(176 citation statements)

References 78 publications

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“…Although some other studies had already looked into the association of dystrophic ferritin + microglia with Aβplaques [6,7,30,39,44], results were inconsistent, as none of these studies so far looked into the relative proportion of these microglia in the total population. The importance of this is also stressed in a recent study by Nguyen et al [45], in which they found an amyloid-responsive microglia (ARM) subset, characterized by CD163, but did not pick up on the Aβ-plaque-infiltrating properties of their identified ferritin + microglia.…”

Section: Discussionmentioning

confidence: 89%

Iron-loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Kenkhuis

Somarakis

Haan

et al. 2021

Preprint

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Brain iron accumulation has been found to accelerate disease progression in Amyloid β-positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key-players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL+Iba1+-microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL+Iba1+-microglia was seen in patients with high Amyloid-β load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.

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Section: Discussionmentioning

confidence: 89%

Iron-loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Kenkhuis

Somarakis

Haan

et al. 2021

Preprint

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“…The importance of this is also stressed in a recent study by Nguyen et al . [ 46 ], in which they found an amyloid-responsive microglia (ARM) subset, characterized by CD163, but did not pick up on the Aβ-plaque-infiltrating properties of their identified ferritin + microglia. Finally, we were able to further characterize iron-positive/FTL + -microglia by analyzing co-expression of several other microglia markers on a single cell level.…”

Section: Discussionmentioning

confidence: 99%

Iron loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Kenkhuis

Somarakis

Haan

et al. 2021

acta neuropathol commun

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Brain iron accumulation has been found to accelerate disease progression in amyloid-β(Aβ) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL+Iba1+-microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL+Iba1+-microglia was seen in patients with high Aβ load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.

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“…Single nuclei RNA-Seq of these genes show that NCK2 is selectively expressed in the AD-relevant cell type, microglia ( Figure 2 ). We examined human cortex samples 46 that included normal tissue without amyloid or tau aggregates (A-T-), tissue with amyloid only (A+T-) and tissue with both amyloid and tau aggregates (A+T+). The highest expression was observed is in amyloid-responsive and homeostatic microglia in tau-negative regions (A+T-).…”

Section: Resultsmentioning

confidence: 99%

“…We examined the effects of variants of interest on levels of microglia subpopulations originally identified using single-nucleus RNA sequencing applied to postmortem human brains from individuals with varied neuropathology and varied APOE and TREM2 genotypes. This approach identified a subpopulation of CD163-positive microglia responsive to amyloid deposition that were significantly attenuated in individuals carrying APOE and TREM2 risk haplotypes/genotypes 46 .…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

Naj

Leonenko

Jian

et al. 2021

Preprint

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Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer's Project (IGAP). Existing genotype data were imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P<10-5 were meta-analyzed with the European Alzheimer's Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10-12), SHARPIN (P=1.56×10-9), and ATF5/SIGLEC11 (P=1.03[mult]10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10-8), APH1B (P=2.10×10-13), and CLNK (P=2.24×10-10). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.

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APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease

Cited by 131 publications

References 78 publications

Iron-loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Iron-loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Iron loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

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