The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging

Abstract

Microglia constitute the primary resident immune surveillance cell in the brain and are thought to play a significant role in the pathogenesis of several neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and HIV-associated dementia. Measuring microglial activation in vivo in patients suffering from these diseases may help chart progression of neuroinflammation as well as assess efficacy of therapies designed to modulate neuroinflammation. Recent studies suggest that activated microglia in the CNS may be detected in vivo using positron emission tomography (PET) utilizing pharmacological ligands of the mitochondrial peripheral benzodiazepine receptor (PBR (recently renamed as Translocator protein (18kDa)). Beginning with the molecular characterization of PBR and regulation in activated microglia, we examine the rationale behind using PBR ligands to image microglia with PET. Current evidence suggests these findings might be applied to the development of clinical assessments of microglial activation in neurological disorders.

Figure 1

The Peripheral Benzodiazepine Receptor is expressed in astrocytes and microglia in the CNS In the resting CNS, PBR expression is thought to be restricted to astrocytes and microglia. PBR is present in the mitochondria of these cells in association with the voltage dependent anion channel and the adenine nucleotide transporter, forming the mitochondrial permeability transition pore. Note that PBR is situated on the outer mitochondrial membrane.

Figure 2

Potential functions and mechanisms of Peripheral Benzodiazepine Receptor increases in activated microglia This figure illustrates potential mechanisms of PBR increases in microglia. The process of activation, in response to neuronal insults, involves cytokine production by microglia. Since, pro-inflammatory cytokines may increase PBR (see text), it is possible that these cytokines act in an autocrine-paracrine fashion to increase PBR expression in microglia that are undergoing activation. The functions of PBR in microglia are unknown. It is possible that PBR plays a yet undefined role in several aspects of microglial function such as the regulation of cell death, proliferation, cytokine and free radical generation.