Characterization of the 18 kDa translocator protein (TSPO) expression in post‐mortem normal and Alzheimer's disease brains

Abstract

The 18 kDa translocator protein (TSPO) is a widely used target for microglial PET imaging radioligands, but its expression in post-mortem normal and diseased human brain is not well described. We aimed at characterizing the TSPO expression in human control (CTRL) and Alzheimer's disease (AD) brains. Specifically, we sought to: (1) define the cell type(s) expressing TSPO; (2) compare tspo mRNA and TSPO levels between AD and CTRL brains; (3) correlate TSPO levels with quantitative neuropathological measures of reactive glia and AD neuropathological changes; and (4) investigate the effects of the TSPO rs6971 SNP on tspo mRNA and TSPO levels, glial responses and AD neuropathological changes. We performed quantitative immunohistochemistry and Western blot in post-mortem brain samples from CTRL and AD subjects, as well as analysis of publicly available mouse and human brain RNA-Seq datasets. We found that: (1) TSPO is expressed not just in microglia, but also in astrocytes, endothelial cells and vascular smooth muscle cells; (2) there is substantial overlap of tspo mRNA and TSPO levels between AD and CTRL subjects and in TSPO levels between temporal neocortex and white matter in both groups; (3) TSPO cortical burden does not correlate with the burden of activated microglia or reactive astrocytes, Aβ plaques or neurofibrillary tangles, or the cortical thickness; (4) the TSPO rs6971 SNP does not significantly impact tspo mRNA or TSPO levels, the magnitude of glial responses, the cortical thickness, or the burden of AD neuropathological changes. These results could inform ongoing efforts toward the development of reactive glia-specific PET radioligands.

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer’s disease: a longitudinal PET study

“…The SVCA modelling approach we used filters out the kinetic components of tracer uptake by endothelial and choroidal epithelium cells though it cannot separate activated astrocyte and microglial signals. Post-mortem studies [35,36] suggest, however, that the major TSPO signal comes from microglia in Alzheimer's disease, but we acknowledge that some of the signal may also reflect activation of astrocytes. It seems reasonable to consider TSPO signal as a marker of intrinsic neuroinflammation.…”

“…11 C-PK11195 PET is strictly a marker of translocator protein (TSPO) expression and not microglial density. Elevations in TSPO are a nonspecific reaction to inflammation, and TSPO is also expressed by cells other than microglia, including activated astrocytes [35]. One, therefore, has to be cautious in interpreting TSPO rises as entirely due to inflammation.…”

Increased Inflammation and Unchanged Density of Synaptic Vesicle Glycoprotein 2A (SV2A) in the Postmortem Frontal Cortex of Alzheimer’s Disease Patients

“…These findings imply that reducing inflammation could play a beneficial role in attenuating tau pathology and synaptic dysfunction in AD. It should be mentioned that a positive correlation between TSPO and pTau immunoreactivity was not observed in the postmortem temporal cortex of AD patients (Gui et al, 2019), suggesting that the interplay between inflammation and tau pathology may occur in a region-specific manner.…”

Cellular sources of TSPO expression in healthy and diseased brain

“…This idea is no longer maintained. Indeed, the presence of TSPO in other cell types, notably astrocytes and endothelial cells, has been demonstrated [4][5][6][7].…”