Lack of support for bexarotene as a treatment for Alzheimer's disease

Eugene O'Hare, Ross Jeggo, Eun-Mee Kim, Bridgeen Barbour, Jean-Sebastien Walczak, Philip Palmer, Taylor Lyons, Deaglan Page, Donncha Hanna, Jolyon R. Meara, David Spanswick, Jian-Ping Guo, Edith G. McGeer, Patrick L. McGeer, Peter Hobson

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.
LanguageEnglish
Pages124-130
Number of pages7
JournalNeuropharmacology
Volume100
Early online date27 May 2015
DOIs
Publication statusPublished - 31 Jan 2016

Fingerprint

Alzheimer Disease
Amyloid
Amyloid Plaques
Conditioned Culture Medium
Transgenic Mice
Aptitude
Long-Term Potentiation
Excitatory Postsynaptic Potentials
bexarotene
Cerebral Cortex
Cognition
Appointments and Schedules
Water
Antibodies
Brain

Keywords

  • Bexarotene
  • Alzheimer's disease
  • Beta-amyloid
  • Oligomers
  • Synaptic transmission
  • Behavior

Cite this

O'Hare, E., Jeggo, R., Kim, E-M., Barbour, B., Walczak, J-S., Palmer, P., ... Hobson, P. (2016). Lack of support for bexarotene as a treatment for Alzheimer's disease. Neuropharmacology, 100, 124-130. https://doi.org/10.1016/j.neuropharm.2015.04.020
O'Hare, Eugene ; Jeggo, Ross ; Kim, Eun-Mee ; Barbour, Bridgeen ; Walczak, Jean-Sebastien ; Palmer, Philip ; Lyons, Taylor ; Page, Deaglan ; Hanna, Donncha ; Meara, Jolyon R. ; Spanswick, David ; Guo, Jian-Ping ; McGeer, Edith G. ; McGeer, Patrick L. ; Hobson, Peter. / Lack of support for bexarotene as a treatment for Alzheimer's disease. In: Neuropharmacology. 2016 ; Vol. 100. pp. 124-130.
@article{39d582d4c3314e9bb36702556f1a7f48,
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.",
keywords = "Bexarotene, Alzheimer's disease, Beta-amyloid, Oligomers, Synaptic transmission, Behavior",
author = "Eugene O'Hare and Ross Jeggo and Eun-Mee Kim and Bridgeen Barbour and Jean-Sebastien Walczak and Philip Palmer and Taylor Lyons and Deaglan Page and Donncha Hanna and Meara, {Jolyon R.} and David Spanswick and Jian-Ping Guo and McGeer, {Edith G.} and McGeer, {Patrick L.} and Peter Hobson",
note = "Accepted 2015",
year = "2016",
month = "1",
day = "31",
doi = "10.1016/j.neuropharm.2015.04.020",
language = "English",
volume = "100",
pages = "124--130",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier",

}

O'Hare, E, Jeggo, R, Kim, E-M, Barbour, B, Walczak, J-S, Palmer, P, Lyons, T, Page, D, Hanna, D, Meara, JR, Spanswick, D, Guo, J-P, McGeer, EG, McGeer, PL & Hobson, P 2016, 'Lack of support for bexarotene as a treatment for Alzheimer's disease', Neuropharmacology, vol. 100, pp. 124-130. https://doi.org/10.1016/j.neuropharm.2015.04.020

Lack of support for bexarotene as a treatment for Alzheimer's disease. / O'Hare, Eugene; Jeggo, Ross; Kim, Eun-Mee; Barbour, Bridgeen; Walczak, Jean-Sebastien; Palmer, Philip; Lyons, Taylor; Page, Deaglan; Hanna, Donncha; Meara, Jolyon R.; Spanswick, David; Guo, Jian-Ping; McGeer, Edith G.; McGeer, Patrick L.; Hobson, Peter.

In: Neuropharmacology, Vol. 100, 31.01.2016, p. 124-130.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lack of support for bexarotene as a treatment for Alzheimer's disease

AU - O'Hare, Eugene

AU - Jeggo, Ross

AU - Kim, Eun-Mee

AU - Barbour, Bridgeen

AU - Walczak, Jean-Sebastien

AU - Palmer, Philip

AU - Lyons, Taylor

AU - Page, Deaglan

AU - Hanna, Donncha

AU - Meara, Jolyon R.

AU - Spanswick, David

AU - Guo, Jian-Ping

AU - McGeer, Edith G.

AU - McGeer, Patrick L.

AU - Hobson, Peter

N1 - Accepted 2015

PY - 2016/1/31

Y1 - 2016/1/31

N2 - 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.

AB - 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.

KW - Bexarotene

KW - Alzheimer's disease

KW - Beta-amyloid

KW - Oligomers

KW - Synaptic transmission

KW - Behavior

UR - https://pure.ulster.ac.uk/en/publications/lack-of-support-for-bexarotene-as-a-treatment-for-alzheimers-dise-3

U2 - 10.1016/j.neuropharm.2015.04.020

DO - 10.1016/j.neuropharm.2015.04.020

M3 - Article

VL - 100

SP - 124

EP - 130

JO - Neuropharmacology

T2 - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -