title: The Continuing Failure of Bexarotene in Alzheimer's Disease Mice.
abstract: Alzheimer's disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance. Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist that increases ApoE expression and microglia phagocytosis has been proposed as a promising therapy for AD, resolving both the amyloid pathology and memory loss. Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD. To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation. No differences were found when specifically investigating the microglial phagocytic state in vivo. In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice. These results suggest that BEXA has no beneficial effects on the multi-factorial pathologic phenotype of AD mice.
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Balducci
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Paladini
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Micotti
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tolomeo
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: La Vitola
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Grigoli
authors.affiliation: Neurosciences Therapeutic Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, UK.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D000077610:Bexarotene; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D000071518:Liver X Receptors; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D047488:Retinoid X Receptors / Q000819:agonists*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D017211:Treatment Failure
chemical_list: D001057:Apolipoproteins E; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene
keywords: Alzheimer’s disease; TASTPM mice; amyloid-β; apolipoprotein E; bexarotene; magnetic resonance imaging; memory; therapy