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.