@misc{oai:repo.qst.go.jp:00071615,
 author = {Barron, Anna and M., GARCIA-SEGURA L. and CARUSO, D. and JAYARAMAN, A. and LEE, J.-W. and C., MELCANGI R. and Ji, Bin and Higuchi, Makoto and Ｂａｒｒｏｎ Ａｎｎａ and 季 斌 and 樋口 真人},
 month = {Nov},
 note = {Translocator protein (TSPO) is a multi-functional mitochondrial transmembrane
protein primarily localised in steroid-producing tissues, including the brain. TSPO ligands elicit
pleiotropic neuroprotective and cognitive benefits mechanistically linked to the regulation of
steroid synthesis and consequently represent emerging treatment strategies for several
neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for
Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864
on the development of neuropathology in the triple transgenic mouse model (3xTgAD). In
3xTgAD mice, the effects of the TSPO ligand on neurosteroidogenesis and AD-related
neuropathology including β-amyloid accumulation, gliosis and behavioral impairment were
examined under both early intervention (7 month-old young-adult male mice with low
pathology) and treatment (24 month-old, aged male mice with advanced neuropathology)
conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology
and behavioral impairment in young adult mice, but also reversed these indices in aged 3xTgAD
mice. In the young-adult mice, these benefits were associated with increased brain levels of the
potent neuroactive steroid hormones, testosterone and progesterone. Because TSPO ligands can
differentially modulate TSPO activities, we also compared the independent and combined effects
of Ro5-4864 with PK-11195 (a non-benzodiazepine TSPO ligand) on endogenous β-amyloid in
wild type mice, finding an additive anti-amyloidogenic effect of combined treatment. To
determine the contribution of increased neurosteroid synthesis to the β-amyloid reducing effects
of Ro5-4864 in the wild type mice, we co-administered Ro5-4864 with a neurosteroidogenesis
inhibitor, aminoglutethimide. We next compared the effect of old (Ro5-4864, PK-11195) and
new-generation TSPO ligands (AC-5216, DAA-1106) on endogenous β-amyloid in wild type
mice. New generation TSPO ligands such as AC-5216 have already undergone significant
clinical development for treatment of anxiety disorders and depression, however our findings
suggest these ligands may also have a therapeutic potential for the treatment of Alzheimer`s., The Society for Neuroscience meeting 2013},
 title = {Ligand of translocator protein stimulates neurosteroid synthesis and reverses pathology in a mouse model of Alzheimer`s disease},
 year = {2013}
}