title: Lack of support for bexarotene as a treatment for Alzheimer's disease.
abstract: Bexarotene has been reported to reduce brain amyloid-β (Aβ) levels and to improve cognitive function in transgenic mouse models of Alzheimer's disease (AD). Four groups failed to fully replicate the primary results but the original authors claimed overall support for the general conclusions. Because of its potential clinical importance, the current work studied the effects of bexarotene using two animal species and highly relevant paradigms. Rats were tested for the ability of bexarotene to prevent changes induced by an Aβ challenge in the form intracerebroventricular (i.c.v) administration of 7PA2 conditioned medium (7PA2 CM) which contains high levels of Aβ species. Bexarotene had no effect on the long-term potentiation of evoked extracellular field excitatory postsynaptic potentials induced by i.c.v. 7PA2 CM. It also had no effect following subcutaneous administration of 2, 5, 10 and 15 mg/kg on behavioral/cognitive impairment using an alternating-lever cyclic-ratio schedule of operant responding in the rat. The effects of bexarotene were further tested using the APPSwFILon, PSEN1*M146L*L286V transgenic mouse model of AD, starting at the time Aβ deposits first begin to develop. Mice were sacrificed after 48 days of exposure to 100 mg bexarotene per day. No significant difference between test and control mice was found using a water-maze test, and no significant difference in the number of Aβ deposits in cerebral cortex, using two different antibodies, was apparent. These results question the potential efficacy of bexarotene for AD treatment, even if instigated in the preclinical period prior to the onset of cognitive deficits reported for human AD. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
authors.affiliation: School of Psychology, Queen's University, University Road, Belfast BT7 1NN, Northern Ireland, UK. Electronic address: e.ohare@qub.ac.uk.
authors.forename: Eugene
authors.initials: E
authors.lastname: O'Hare
authors.affiliation: Neurosolutions Limited, P.O. Box 3517, Coventry CV4 7ZS, UK. Electronic address: r.jeggo@neurosolutionsltd.com.
authors.forename: Ross
authors.initials: R
authors.lastname: Jeggo
authors.affiliation: School of Psychology, University of Ulster, Cromore Road, Coleraine BT52 1SA, UK. Electronic address: e.kim@ulster.ac.uk.
authors.forename: Eun-Mee
authors.initials: EM
authors.lastname: Kim
authors.affiliation: School of Psychology, Queen's University, University Road, Belfast BT7 1NN, Northern Ireland, UK. Electronic address: bmcmahon09@qub.ac.uk.
authors.forename: Bridgeen
authors.initials: B
authors.lastname: Barbour
authors.affiliation: Cerebrasol Limited, P.O. Box 63534, Montreal Quebec H3W1JO, Canada. Electronic address: jswalczak@cerebrasol.com.
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Walczak
authors.affiliation: School of Psychology, Queen's University, University Road, Belfast BT7 1NN, Northern Ireland, UK. Electronic address: ppalmer01@qub.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Palmer
authors.affiliation: School of Psychology, Queen's University, University Road, Belfast BT7 1NN, Northern Ireland, UK. Electronic address: tlyons03@qub.ac.uk.
authors.forename: Taylor
authors.initials: T
authors.lastname: Lyons
authors.affiliation: School of Psychology, Queen's University, University Road, Belfast BT7 1NN, Northern Ireland, UK. Electronic address: d.page@qub.ac.uk.
authors.forename: Deaglan
authors.initials: D
authors.lastname: Page
authors.affiliation: School of Psychology, Queen's University, University Road, Belfast BT7 1NN, Northern Ireland, UK. Electronic address: donncha.hanna@qub.ac.uk.
authors.forename: Donncha
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Institute of Primary Care and Public Health, Cardiff University CF10 3XQ, UK. Electronic address: jolyon.meara@wales.nhs.uk.
authors.forename: Jolyon R
authors.initials: JR
authors.lastname: Meara
authors.affiliation: Neurosolutions Limited, P.O. Box 3517, Coventry CV4 7ZS, UK; Cerebrasol Limited, P.O. Box 63534, Montreal Quebec H3W1JO, Canada; Department of Physiology, Monash University, Clayton VIC 3800, Australia. Electronic address: david.spanswick@monash.edu.
authors.forename: David
authors.initials: D
authors.lastname: Spanswick
authors.affiliation: Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver V6T1Z3, BC, Canada.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Guo
authors.affiliation: Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver V6T1Z3, BC, Canada.
authors.forename: Edith G
authors.initials: EG
authors.lastname: McGeer
authors.affiliation: Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver V6T1Z3, BC, Canada. Electronic address: mcgeerpl@mail.ubc.ca.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
authors.affiliation: Institute of Primary Care and Public Health, Cardiff University CF10 3XQ, UK. Electronic address: peter.hobson@wales.nhs.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Hobson
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000077610:Bexarotene; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016466:CHO Cells; D003216:Conditioning, Operant / Q000187:drug effects; D003412:Cricetulus; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*
chemical_list: D016229:Amyloid beta-Peptides; D017077:Culture Media, Conditioned; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene
keywords: Alzheimer's disease; Behavior; Beta-amyloid; Bexarotene; Oligomers; Synaptic transmission