125 TSPO expression in healthy and diseased brain Table 2. TSPO cell origin in human neurological diseases. Human disease Microglia Astrocytes Neurons Endothelial VSMCs Refs Neuroinflammation MS x x 6,171 Neurodegenerative AD x x x x 175,176 LBD x 176 Infections HIV x x x x 168 CreutzfeldtJakob x 177 Neuropsychiatric MDD x 178-180 Stroke x x 168 Epilepsy x x x 181 Abbreviations: AD = Alzheimer’s disease, HIV = Human immunodeficiency virus, LBD = Lewy-body dementia, MDD = Major depressive disorder, MS = Multiple sclerosis, VSMCs = vascular smooth muscle cells in astrocytes, predominantly in chronic active and inactive lesions, and that the astrocyte signal contributes significantly to the active lesions and rim of chronic active lesions. In addition, this study highlights that TSPO is expressed in some but not all M1 (pathogenic) and M2 (immune-regulatory) phenotypes as well as intermediate microglia/macrophages171,172. Furthermore, a percentage of both TMEM119+ and P2RY12+ cells, markers that represent homeostatic microglia, express TSPO in MS lesions indicating that TSPO PET is not merely a reflection of pathogenic microglia, although the trigger of TSPO upregulation in MS CNS is still unclear. In addition, in MS, TSPO is also expressed by T and B cells in the CNS and thus such cellular expression during disease must be considered in TSPO PET imaging. Neurodegenerative Diseases An association between microglia activation, astrogliosis, and neuronal damage has been reported for several neurodegenerative diseases, e.g. AD, Parkinson’s disease, and Amyotrophic lateral Sclerosis (ALS; motor neuron disease)173. As with MS, TSPO PET imaging is widely-considered to reflect the pathogenic microglia in neurodegenerative diseases in vivo. Using post-mortem brain tissues, several studies have used autoradiography to determine TSPO density in human brain tissues but few have examined the cellular distribution in detail (reviewed by 174). Recently, a study using immunohistochemistry on AD human brain tissues revealed TSPO expression by microglia, astrocytes, endothelial cells, and vascular smooth muscle cells175. TSPO expression was not quantified by cell counts but rather by the amount of TSPO immunoreactivity. Although the authors reported a slight increase of TSPO immunoreactivity in the grey matter compared to healthy subjects, such expression was not associated with Braak stage, Aβ plaques or neurofibrillary tangles or cortical thickness. While these authors showed TSPO expression by CD68 and IBA1+ microglia/macrophages, they did not examine expression in specific microglia phenotypes. Receptor density was not found to be increased in post-mortem AD brain or in dementia with Lewy-bodies (DLB) as investigated with quantitative autoradiography176. Interestingly, a significant decrease in receptor density or receptor binding was found in the substantia nigra of AD and DLB. No studies have been conducted to investigate the TSPO expression at the cellular level in other neurodegenerative diseases such as ALS, Huntington’s disease, or spinocerebellar atrophy. Infections TSPO expression in the CNS of a few cases with HIV was reported to be similar to healthy human brain168. TSPO is reported in metabolic glia, a form of reactive astrocyte, and microglial cells. Tissues from HIV encephalitis (HIVE) cases revealed an increased expression of TSPO in
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