Microglial proteins Iba1 and TSPO (PBR) are differentially altered in the temporal cortex and cerebellum according to Braak stage

Abstract

AbstractBackgroundMicroglia are the resident immune cells in the brain and contribute to the neuropathology of Alzheimer’s disease (AD) by mechanisms not completely known. Iba1 is a microglial marker associated with homeostatic and motility functions. Whereas TSPO (PBR) is a marker of the mitochondrial membrane in microglia, macrophages and endothelial cells and is proposed to be associated with the activated subtype of microglia.MethodTo assess both Iba1 and PBR, we retrieved human temporal cortex and cerebellum samples from 57 cases at different stages of the disease, based on the Braak staging (Group 0‐II n=19, Group III‐IV n=20, Group V‐VI n=18), using immunohistochemical analysis. Additionally, a V‐Plex Mesoscale Discovery (MSD) analysis was performed to assess the inflammatory environment.ResultThere was a significant increase in PBR percentage load (P<0.001) across the Braak stages in the temporal cortex (average load 0.93%) but not in the cerebellum (average load 0.76%). Conversely, there was a significant increase in cerebellar Iba1 load (average load 0.96%, P=0.012) but not in the temporal cortex (average load 1.12%). Furthermore, it was observed that Iba1 forms clusters, putatively around amyloid plaques, whereas this phenomenon was not seen with the PBR marker. The only significant inflammatory molecule was the cytokine IL15 in the temporal cortex (P=0.024), which increased across all Braak stages. However, when the MSD data was correlated with the Iba1 and PBR markers it showed that GM‐CSF was significantly correlated with PBR in the temporal cortex (P<0.0099) and IL‐16 was significantly correlated with Iba1 in the cerebellum (P<0.0012).ConclusionThis emphasises the outcome that, in AD, PBR may contribute to inflammation in the temporal cortex and Iba1 may be correlated to inflammation in the cerebellum. The findings indicate that TSPO relates to microglial activation in the brain which is Braak‐stage specific and consequently supports the use of TSPO ligands for positron emission tomography (PET) imaging of Alzheimer’s disease‐relevant microglial activity in vivo. Moreover, the absence of an increase in PBR load in the cerebellum could qualify this structure as a reference region for PET quantification.