title: Ligand for translocator protein reverses pathology in a mouse model of Alzheimer's disease.
abstract: Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that 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 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. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in nontransgenic mice. These findings suggest that TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Barron
authors.forename: Luis M
authors.initials: LM
authors.lastname: Garcia-Segura
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.forename: Anusha
authors.initials: A
authors.lastname: Jayaraman
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Roberto C
authors.initials: RC
authors.lastname: Melcangi
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Pike
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001570:Benzodiazepinones / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D007546:Isoquinolines / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009919:Orchiectomy; D053764:Presenilin-1 / Q000235:genetics; D018079:Receptors, GABA / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001570:Benzodiazepinones; C463819:Bzrp protein, mouse; D007546:Isoquinolines; C508853:PSEN1 protein, human; D053764:Presenilin-1; D018079:Receptors, GABA; D013256:Steroids; D016875:tau Proteins; C028513:4'-chlorodiazepam; C037850:PK 11195