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TSPO/123I-­CLINDE an inflammatory marker in a murine model of Alzheimer's disease? A neuropathological and a SPECT study

Master program titleMaster en neuroscience
Defense date2016
Abstract

Alzheimer's disease (AD) is an age-dependent and irreversible neurodegenerative disorder that causes a progressive deterioration of cognitive functions. The neuropathological lesions of AD comprise amyloid deposits, in form of either diffuse or dense core amyloid-β (Aβ) plaques, and neurofibrillary tangles (NFT), which consist in hyperphosphorylated tau aggregates. Inflammatory processes have been implicated in initiating and/or propagating AD. Among inflammatory markers, there is a mitochondria protein expressed in microglia called translocator protein (TSPO 18kDa). Activated microglia and reactive astrocytes show an increase in TSPO levels. A new Single Photon Emission Tomography (SPECT) radioligand was produced to target TSPO: 6-chloro-2- (4′iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide or 123 I-CLINDE. Until now, 123 I-CLINDE was tested only in rat and mouse models of inflammation. Therefore, we decided to use the 3xTg-AD mouse model, which harbors the most similar pathological features to human AD, to test CLINDE as a marker of inflammation in AD. Immunohistochemistry (IHC) and Western-blots (WB) were carried out to evaluate the presence of TSPO in 3xTg-AD mice and control mice Sv-129 at three different ages: young mice of 1-2 months where the pathology is still not present, middle age mice of 12-13 months where Aβ plaques and NFT start to appear and old mice of 19-21 months where the whole pathology is expressed. IHC revealed the presence of TSPO in the hippocampus of 12 months old 3xTg-AD mice and a very weak signal in matched control Sv-129; at 19-21 months TSPO positive cell are present in the hippocampus of both groups of mice. These results are confirmed by WB but with inter-subject variability. In vivo analysis of TSPO using the SPECT with 123I-CLINDE was subsequently carried out. No specific signal was detected at any age. In order to explain the absence of clear brain signal, plasma kinetics of 123I-CLINDE was carried out in a rat. Indeed 123I-CLINDE was trapped in red blood cells and the plasmatic concentration is under 10% of the injected dose. Thus there was a clear-cut red cells trapping of the CLINDE unsuitable for SPECT imaging. Nevertheless, ex vivo autoradiography analysis of brain after 123I-CLINDE injections showed increased intensities in the dorsal and lateral hippocampus since 12 months of age. Finally, in vitro autoradiography was performed showing an increased 123I-CLINDE binding in hippocampus of 3xTg-AD mice compared to controls along aging. This increase was earlier in the dorsal hippocampus than in the ventral hippocampus. The results of the autoradiography in vitro were compatible with those of the IHC and WB. Overall, we demonstrated that 123I-CLINDE is not appropriate as an in vivo marker of inflammation for AD. But it allows to furthermore describe the progression of inflammation in 3xTg-AD mice that is apparent since 12-13 months.

eng
Keywords
  • TSPO
  • Alzheimer
  • SPECT
  • CLINDE
Citation (ISO format)
RIGAUD SORIANO, Daphnéy. TSPO/123I-­CLINDE an inflammatory marker in a murine model of Alzheimer’s disease? A neuropathological and a SPECT study. 2016.
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Master thesis
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  • PID : unige:93845
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