Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Abstract

Microglial activation plays central roles in neuro-inflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. For the first time, we show that TSPO gene and protein expression increases in activated microglia in mouse brain disease models postmortem, but does not change in a non-human primate (Callithrix jacchus) disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter that may be responsible for this, which is consistent with the hypothesis that the increase in TSPO in activated myeloid cells is unique to a subset of species within the Muroidea superfamily of rodents. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO PET reflects density of inflammatory cells rather than their activation state.

APOE ε4 gene dose effect on imaging and blood biomarkers of glial reactivity and β-amyloid pathology

“…This is not surprising, considering that plasma GFAP is expected to reflect more astrocytic reactivity associated with Aβ pathology, 39 whereas TSPO PET is thought to reflect microglial density. 20 Our results with GFAP support the previous findings suggesting that reactive astrocytosis is present already in cognitively normal individuals and related to Aβ pathology. 37, 39, 63…”

“…TSPO is present in the outer mitochondrial membranes of microglia and elevated in the brain in relation to injuries or pathology 19 . In humans, increased TSPO ligand-binding has recently been suggested to represent changes in cell density rather than protein overexpression 20 , and to be mostly covered by microglia, and to a lesser extent astrocytes and endothelial cells 21, 22 . Previous studies using TSPO PET imaging have shown increased regional ligand-binding in patients with Alzheimer’s disease 23-26 , mild cognitive impairment 4, 27, 28 and in Aβ-positive compared with -negative controls 7, 29 .…”

Brain and systemic inflammation in de novo Parkinson’s disease

“…For many years, TSPO was thought to be specific to microglial activation, yet TSPO can also be bound by other inflammatory cells, including astrocytes and peripheral immune cells 73-76 . More recent studies in rodent models have suggested that TSPO signal may be related more to microglial number than microglial activation 77 . While our observations suggest that increased TSPO signal reflects central inflammation and correlates with cognitive measures, the TSPO signal we observed is found in multiple brain regions and does not offer clear insight into the cell types that may be responsible.…”

[64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation

“…More importantly, TSPO PET was found to reflect the density of inflammatory cells rather than their activation in humans, because its expression in human myeloid cells is related to different phenomena. Therefore, TSPO PET can reflect activated microglia in rodents but not in humans, which means the interpretation of TSPO PET data requires revision [19]. Therefore, more neuroimmune imaging biomarkers are necessary to overcome the limitation of TSPO PET.…”