title: Neuronally-directed effects of RXR activation in a mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age. Moreover, bexarotene treatment improved remote memory stabilization in fear conditioned mice and improved olfactory cross habituation. These improvements in neuron viability and function were correlated with significant increases in the levels of post-synaptic marker PSD95 and the pre-synaptic marker synaptophysin. Moreover, bexarotene pretreatment improved neuron survival in primary 5XFAD neurons in vitro in response to glutamate-induced excitotoxicity. The salutary effects of bexarotene were accompanied by reduced plaque burden, decreased astrogliosis, and suppression of inflammatory gene expression. Collectively, these data provide evidence that bexarotene treatment reduced neuron loss, elevated levels of markers of synaptic integrity that was linked to improved cognition and in an aggressive model of AD.
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Mariani
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.|A.I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Malm
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lamb
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Jay
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: L
authors.initials: L
authors.lastname: Neilson
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: B
authors.initials: B
authors.lastname: Casali
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: L
authors.initials: L
authors.lastname: Medarametla
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000077610:Bexarotene; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D018698:Glutamic Acid / Q000633:toxicity; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D009830:Olfactory Bulb / Q000187:drug effects / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D015415:Biomarkers; D016207:Cytokines; D026901:Membrane Transport Proteins; D009498:Neurotoxins; D011973:Receptors, LDL; D047488:Retinoid X Receptors; C491168:Sorl1 protein, mouse; D013764:Tetrahydronaphthalenes; D018698:Glutamic Acid; D000077610:Bexarotene