Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer’s Disease Pathology in Down Syndrome

Raha-Chowdhury, Ruma; Henderson, James W.; Raha, Animesh Alexander; Stott, Simon; Vuono, Romina; Foscarin, Simona; Wilson, Liam R.; Annus, Tiina; Fincham, Robert; Allinson, Kieren; Devalia, Vinod; Friedland, Robert P.; Holland, Anthony; Zaman, Shahid

doi:10.3233/jad-170814

Cited by 28 publications

(41 citation statements)

References 61 publications

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“…Plasma sTREM2 was significantly elevated in DS, in agreement with previously described elevation of sTREM2 in DS sera from young adults with DS prior to dementia onset 33 . Interestingly, sTREM2 is elevated in cerebrospinal fluid in the mild cognitive impairment stage of AD and in early onset forms of AD, but not in peripheral biofluids, such as plasma 24,25,27,28,54 .…”

Section: Discussionsupporting

confidence: 91%

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Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Weber

Koenig

Khrestian

et al. 2019

Preprint

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Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) -related neuropathology, characterized by amyloid plaques with amyloid β (Aβ) and neurofibrillary tangles with tau accumulation more frequently and at an earlier age than their neurotypical counterparts. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble cleavage product of TREM2 (sTREM2) has been described as elevated in AD cerebrospinal fluid and positively correlates with Aβ and cognitive decline. There is relatively little information about TREM2 in DS. The objective of this study was to examine the relationship between sTREM2 and inflammatory markers in DS, prior to the development of dementia symptoms. Since TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS pre-dementia (n=15, mean age 29.5 years) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared to neurotypical, agematched controls (n=16, mean age 29.6 years). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. In addition, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, while there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the group with DS and controls, supporting the hypothesis that its function is altered in people with DS predementia. This exploratory study provides a basis for future studies investigating the relationship between TREM2 and the broader immune response pre-dementia.

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Section: Discussionsupporting

confidence: 91%

“…The soluble cleavage product of TREM2 (sTREM2) is elevated in AD cerebrospinal fluid and positively correlates with Aβ and cognitive decline [24][25][26][27][28][29][30][31][32] . There is relatively little information about TREM2 in DS, though one group describes elevated sTREM2 in young adults and declining levels with aging 33,34 .…”

Section: Introductionmentioning

confidence: 99%

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Weber

Koenig

Khrestian

et al. 2019

Preprint

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“…There have been some studies that report to show human TREM2 immunohistochemistry but with varying results (12,51). Most recently Raha-Chowdhury et al (47,48) have shown some immunohistochemistry with TREM2 in human tissue but it is unknown how well this was characterised. There has been some debate in the field when some of these studies were published that TREM2 was only expressed in monocytes, hence the staining pattern separate to microglia (7,12,51).…”

Section: Discussionmentioning

confidence: 99%

Investigation of pathology, expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer’s disease

et al. 2020

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Triggering receptor expressed on myeloid cells 2 TREM2 was identified as a risk factor for late onset Alzheimer's disease (AD). Here we compared TREM2 cases with a variant (TREM2 +) and cases without a TREM2 variant (TREM2 −), considering pathological burden, inflammatory response and altered canonical pathways and biochemical functions between the cohorts. We hypothesised that TREM2 + cases would have a loss of function, indicating an altered inflammatory profile compared to TREM2 − cases. Immunohistochemistry was performed using antibodies against Aβ, tau and microglia markers in TREM2 + cases, with and without AD, which were compared to sporadic TREM2 − AD, familial AD and neurologically normal control cases. Aβ and tau load were measured along with the composition of Aβ plaques, in addition to microglial load and circularity. Expression and proteomic profiles were determined from the frontal cortex of selected cases. TREM2 + control cases had no Aβ or tau deposition. No differences in the amount of Aβ or tau, or the composition of Aβ plaques were observed between TREM2 + and TREM2 − SAD cases. There were no differences in microglial load observed between disease groups. However, the TREM2 + SAD cases showed more amoeboid microglia than the TREM2 − SAD cases, although no differences in the spatial relationship of microglia and Aβ plaques were identified. Visualisation of the canonical pathways and biological functions showed differences between the disease groups and the normal controls, clearly showing a number of pathways upregulated in TREM2 + SAD, TREM2 − SAD and FAD groups whilst, the TREM2 + controls cases showed a downregulation of the majority of the represented pathways. These findings suggest that the TREM2 + control group, although carrying the TREM2 + variant, have no pathological hallmarks of AD, have altered microglial and expression profiles compared to the TREM2 + SAD cases. This indicates that other unknown factors may initiate the onset of AD, with TREM2 influencing the microglial involvement in disease pathogenesis.

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“…A drop of blood placed on a slide was spread using a spreader as described previously [29]. The slide was air-dried and fixed in 100% methanol and stored at 4°C.…”

Section: Blood Slide Preparationmentioning

confidence: 99%

“…We found that CD26 is expressed in the epithelial membrane of the choroid plexus (CP) and in the endothelium of blood vessels in the brain. The CP is a secretory tissue responsible for producing both the CSF in the vertebrate brain and many innate immune molecules to protect the brain from infection by surveilling the blood brain barrier (BBB) [29,68]. CD26 protein is present in the CP epithelial membrane and in the outer layer of brain pia mater particularly in the meningeal macrophages, where it is colocalised with other brain spectrins, known as fordin and ankyrin [29,69].…”

Section: Recently Sequence and Modeling Analysis Of S Glycoproteins mentioning

confidence: 99%

Investigation of CD26, a potential SARS-CoV-2 receptor, as a biomarker of age and pathology

et al. 2020

Self Cite

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Objective: In some individuals, coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leads to a variety of serious inflammatory symptoms, including blood clotting and acute respiratory distress. Death due to COVID-19 shows a steep rise in relation to age. Comorbidities such as type 2 diabetes mellitus (T2DM), hypertension, and cardiovascular disease also increase susceptibility. It has been reported that T-cell regulatory dipeptidyl peptidase 4 (DPP4; cluster of differentiation 26 (CD26)) binds to the external spike (S) glycoprotein of SARS-CoV-2 as a receptor, for the viral entry into the host cell. CD26 is expressed on many cells, including T and natural killer (NK) cells of the immune system, as a membrane-anchored form. A soluble form (sCD26) is also found in the blood plasma and cerebrospinal fluid (CSF). Approach and results: To investigate a possible relationship between sCD26 levels, age and pathology, serum samples were collected from control, T2DM and age-related dementia (ARD) subjects. A significant reduction in serum sCD26 levels was seen in relation to age. ARD and T2DM were also associated with lower levels of sCD26. The analysis of blood smears revealed different cellular morphologies: in controls, CD26 was expressed around the neutrophil membrane, whereas in T2DM, excessive sCD26 was found around the mononucleated cells (MNCs). ARD subjects had abnormal fragmented platelets and haemolysis due to low levels of sCD26. Conclusions: These findings may help to explain the heterogeneity of SARS-CoV-2 infection. High serum sCD26 levels could protect from viral infection by competively inhibiting the virus binding to cellular CD26, whereas low sCD26 levels could increase the risk of infection. If so measuring serum sCD26 level may help to identify individuals at high risk for the COVID-19 infection.

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Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer’s Disease Pathology in Down Syndrome

Cited by 28 publications

References 61 publications

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Investigation of pathology, expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer’s disease

Investigation of CD26, a potential SARS-CoV-2 receptor, as a biomarker of age and pathology

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