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Title: Therapeutic effects and potential use of imidazoline receptors and TSPO ligands as PET tracers for gliosis in mouse models of AD
Author: Mirzaei, Nazanin
ISNI:       0000 0004 7655 5336
Awarding Body: University of London
Current Institution: Imperial College London
Date of Award: 2018
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Alzheimer’s disease (AD) pathogenesis is associated with a chronic inflammatory response, supported by the presence of activated astrocytes and microglia surrounding amyloid plaques in the brain of AD patients and animal models of the disease. Previous studies have shown increased TSPO expression in activated microglia and there is evidence suggesting the density of type-2 imidazoline receptors (I2IR) may serve as a marker for astrocytes. In addition, I2IR ligands have shown neuroprotective properties in several animal models of CNS injury. In this study, our aim was to 1) evaluate the suitability of two PET radioligands, TSPO-specific tracer [11C]PBR28 and I2IR-selective tracer [11C]BU99008, for the in vivo visualization and quantification of activated microglia and astrocytes in the AD brain, respectively; 2) investigate the putative beneficial effects of chronic treatment with the I2IR-selective ligand BU224 in the 5XFAD mouse model of AD. We found significantly higher brain retention of [11C]PBR28 in the 5XFAD transgenic mouse model of AD compared with wild-type (WT) control mice, indicating a higher brain density of TSPO in the transgenic AD animals. This was confirmed by visualization of TSPO, using [3H]PBR28, in brain tissue of scanned mice. The spatial pattern of TSPO enrichment coincided with higher microglial density in regions of extensive amyloid deposition. In post-mortem AD brain tissue, a higher I2IR density was detected by [3H]BU99008, particularlyin regions enriched in astrocytes. However, no correspondence between I2IR density and astrocyte density was found in the mouse brain. Chronic treatment with I2IR ligand BU224 in 5XFAD mice at severe stages of the disease resulted in the reversal of impairments in memory and hippocampal neurogenesis, reduced microgliosis, down-regulation of pro-inflammatory cytokines and increases in synaptic density. In conclusion, we provide evidence for the feasibility of longitudinal TSPO PET imaging using [11C]PBR28 in live mice to monitor changes in levels of microglial activation, and the potential use of [11C]BU99008 for the detection of astrocytes in AD patients, but not mouse models of the disease. Our findings also provide novel support for the association of I2IRs and neurodegenerative disorders and suggest a new therapeutic target for the clinical treatment of AD, even at severe stages of disease with high amyloid burden in the brain.
Supervisor: Sastre, Magdalena ; Reynolds, Richard ; Nutt, David Sponsor: Edmond J. Safra Philanthropic Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral