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

Abstract

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.

Mechanisms contributing to differential genetic risks for TREM2 R47H and R62H variants in Alzheimer’s Disease

“…We did not find differences in neuronal nuclei relative numbers in TREM2var NDC tissue relative to CV implying that TREM2 var neurotoxicity arises with increased amyloid/pTau, consistent with the view that TREM2var are genetic susceptibility factors rather than independently causal factors for disease. Although our neuropathological and transcriptomic observations of amyloid and microglial activation differences with TREM2var are similar to those reported in previous studies 9,15–17 , our comparison of R47H and R62H is novel. We have related microglial activation differences with AD pathology to those in astrocytes for the first time.…”

“…Although our neuropathological and transcriptomic observations of amyloid and microglial activation differences with TREM2var are similar to those reported in previous studies 9, [15][16][17] , our comparison of R47H and R62H is novel. We have related microglial activation differences with AD pathology to those in astrocytes for the first time.…”

“…These have either not shown differences or have reported increased amyloid load and glial inflammatory activation with TREM2var relative to CV [15][16][17][18] . Neuronal tau pathology with TREM2 R47H and R62H was reported to show no change 15,16 or a decrease 17 relative to CV. Studies of human AD post-mortem tissue with both variants have described greater neuronal loss 11,17,19 .…”

“…Fewer studies of the impact of these variants in human tissue have been reported. These have either not shown differences or have reported increased amyloid load and glial inflammatory activation with TREM2var relative to CV [15][16][17][18] . Neuronal tau pathology with TREM2 R47H and R62H was reported to show no change 15,16 or a decrease 17 relative to CV.…”

Understanding microglial diversity and implications for neuronal function in health and disease

“…Trem2 , a key AD risk gene (Guerreiro, Wojtas, et al, 2013 ; Jonsson et al., 2013 ), appears to be critical for this “sensing” ability and downstream damage response. Mice with defective TREM2 signaling display impaired microglial response to injury and amyloid plaque pathology (Kleinberger et al., 2017 ; Ulland et al., 2017 ; Wang et al., 2015 ), a phenotype also demonstrated in human AD brain tissue (Toomey et al., 2020 ; Ulrich et al., 2014 ; Wang et al., 2016 ) (for a recent review on TREM2, please refer to: Deczkowska, Weiner, & Amit, 2020 ). Further, TREM2 is vital for sensing damaged lipids (Wang et al., 2015 ), maintaining proper lipid homeostasis (Jaitin et al., 2019 ; Nugent et al., 2020 ) and sustaining energy metabolism (Ulland et al., 2017 ).…”