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

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 A beta, 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. A beta and tau load were measured along with the composition of A beta 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 A beta or tau deposition. No differences in the amount of A beta or tau, or the composition of A beta 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 A beta 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.