Neuroprotective effect of mitochondrial translocator protein ligand in a mouse model of tauopathy
| Autor: | Makoto Higuchi, Lauren H. Fairley, Tetsuya Suhara, Naruhiko Sahara, Ichio Aoki, Bin Ji, Anna M. Barron |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cell Survival
Immunology Complement tau Proteins Ligands Neuroprotection lcsh:RC346-429 Cellular and Molecular Neuroscience Amyloid beta-Protein Precursor Atrophy Receptors GABA Neuroinflammation medicine Translocator protein lcsh:Neurology. Diseases of the nervous system biology Microglia Chemistry General Neuroscience Research Neurodegeneration Brain medicine.disease Magnetic Resonance Imaging Cell biology medicine.anatomical_structure Neuroprotective Agents Neurology Tauopathies Positron-Emission Tomography biology.protein Tauopathy NeuN Tau Alzheimer’s disease TSPO Peripheral benzodiazepine receptor |
| Zdroj: | Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-13 (2021) Journal of Neuroinflammation |
| ISSN: | 1742-2094 |
| Popis: | Background The translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer’s disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer’s beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg). Methods Brain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice. Results TSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy. Conclusions These findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy. |
| Databáze: | OpenAIRE |
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