Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer’s disease patient brain samples

Prokop, Stefan; Miller, Kelly R.; Labra, Sergio R.; Pitkin, Rose M.; Hoxha, Kevt’her; Narasimhan, Sneha; Changolkar, Lakshmi; Rosenbloom, Alyssa B.; Lee, Virginia M.‐Y.; Trojanowski, John Q.

doi:10.1007/s00401-019-02048-2

Cited by 75 publications

(76 citation statements)

References 62 publications

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“…Altered microglial response to β -amyloid plaques due to T2D has been suggested earlier, although no quantitative data have been presented [96]. Interestingly, increased microglial dystrophy has been reported in the hypothalamus of obese individuals [3] as well as in the hippocampus and several cortical areas in AD patients [76,91]. Collectively, our results together with previous studies in both mouse and human support the idea that obesity and T2D contribute to microglial dysfunction.…”

Section: Discussionsupporting

confidence: 81%

Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques

Natunen

Martiskainen

Marttinen

et al. 2020

Preprint

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Section: Discussionsupporting

confidence: 81%

Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques

Natunen

Martiskainen

Marttinen

et al. 2020

Preprint

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“…Interestingly, a recent study reports more hyperphosphorylated tau in the cortex of an AD mouse model carrying the human TREM2 R47H variant, which was thought to result from a reduction of microgliosis around amyloid‐β plaques. This in turn could facilitate the local seeding and spreading of tau, findings which were also reported in the AD patient brain where a reduced microglial accumulation around plaques associated with higher pathological tau burden was found in TREM2 R47H HD patients . However, it still remains unclear as to why TREM2 seems to influence only cognition and not motor decline in our HD study, but it could relate to an effect it may have on the distribution of pathology.…”

Section: Discussionsupporting

confidence: 58%

“…53 As such, similar mechanisms related to the triggered activation of microglia by mutant huntingtin protein could underlie the more severe cognitive decline in patients with the findings which were also reported in the AD patient brain where a reduced microglial accumulation around plaques associated with higher pathological tau burden was found in TREM2 R47H HD patients. 55 However, it still remains unclear as to why TREM2 seems to influence only cognition and not motor decline in our HD study, but it could relate to an effect it may have on the distribution of pathology. Although the postmortem samples available for our study does not allow one to conclude on TREM2 cortical expression levels in HD nor to assess whether such a reduction of microgliosis around mutant huntingtin protein inclusions exists in the cortex of TREM2 R47H HD patient carriers, it will be interesting to look at whether this could underlie the link between the more aggressive cognitive decline suggested by our genotype-phenotype study in TREM2 R47H HD patients.…”

Section: Discussionmentioning

confidence: 69%

Association Between Toll‐Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease

et al. 2019

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Background Although Huntington's disease (HD) is caused by a single dominant gene, it is clear that there are genetic modifiers that may influence the age of onset and disease progression. Objectives We sought to investigate whether new inflammation‐related genetic variants may contribute to the onset and progression of HD. Methods We first used postmortem brain material from patients at different stages of HD to look at the protein expression of toll‐like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2). We then genotyped the TREM2 R47H gene variant and 3 TLR4 single nucleotide polymorphisms in a large cohort of HD patients from the European Huntington's Disease Network REGISTRY. Results We found an increase in the number of cells expressing TREM2 and TLR4 in postmortem brain samples from patients dying with HD. We also found that the TREM2 R47H gene variant was associated with changes in cognitive decline in the large cohort of HD patients, whereas 2 of 3 TLR4 single nucleotide polymorphisms assessed were associated with changes in motor progression in this same group. Conclusions These findings identify TREM2 and TLR4 as potential genetic modifiers for HD and suggest that inflammation influences disease progression in this condition. © 2019 International Parkinson and Movement Disorder Society

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“…Laser capture microdissection (LCM) is one method that can be used to isolate cell types and quantify protein and gene expression in distinct populations of cells, though it is technically challenging and difficult to scale 8 . NanoString Digital Spatial Profiling (DSP) is a highly multiplexed method that allows for protein quantification in spatially resolved, morphologically distinct areas within a single FFPE tissue section 9,[11][12][13][14][15] . This method utilizes UV-photocleavable oligonucleotides that are conjugated to primary antibodies [13][14][15] .…”

mentioning

confidence: 99%

Spatially-resolved quantification of proteins in triple negative breast cancers reveals differences in the immune microenvironment associated with prognosis

Stewart

Matynia

Factor

et al. 2020

Sci Rep

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Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. Recent studies have shown that MHC class II (MHCII) expression and tumor infiltrating lymphocytes are important prognostic factors in patients with TNBC, although the relative importance of lymphocyte subsets and associated protein expression is incompletely understood. NanoString Digital Spatial Profiling (DSP) allows for spatially resolved, highly multiplexed quantification of proteins in clinical samples. In this study, we sought to determine if DSP could be used to characterize expression of MHCII and other immune related proteins in tumor epithelial versus stromal compartments of patient-derived TNBCs (N = 10) using a panel of 39 markers. We confirmed that a subset of TNBCs have elevated expression of HLA-DR in tumor epithelial cells; HLA-DR expression was also significantly higher in the tumors of patients with long-term disease-free survival when compared to patients that relapsed. HLA-DR expression in the epithelial compartment was correlated with high expression of CD4 and ICOS in the stromal compartment of the same tumors. We also identified candidate protein biomarkers with significant differential expression between patients that relapsed versus those that did not. In conclusion, DSP is a powerful method that allows for quantification of proteins in the immune microenvironment of TNBCs.

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Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer’s disease patient brain samples

Cited by 75 publications

References 62 publications

Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques

Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques

Association Between Toll‐Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease

Spatially-resolved quantification of proteins in triple negative breast cancers reveals differences in the immune microenvironment associated with prognosis

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