Bexarotene improves behavior and neuron health in 5XFAD mice
Case Western Reserve University School of Medicine
Supervising Advisor: Dr. Gary Landreth
Alzheimer’s disease (AD) is a devastating neurodegenerative disease that results in progressive memory impairment, cognitive deficits and eventually death. We have reported that the Retinoid X Receptor activator, bexarotene, rapidly reversed the memory and cognitive deficits and attenuated the pathological effects of the disease in mouse models of AD. During this fellowship, we will determine if Bexarotene can prevent or ameliorate neuronal death in a mouse model of AD. This is important because there are very few mouse models of AD which have significant neuronal death, and determining if Bexarotene can improve neuron health. We propose to examine the cellular mechanisms through which the drug acts to clear intracellular deposits of amyloid in neurons and promote their survival. These studies are of importance as they will provide proof of principal evidence for the potential utility of bexarotene in treating individuals at advanced stages of the disease and inform the design of future AD clinical trials.
The work supported by the Weston Foundation Advisor Fellowship was focused on determining if an FDA approved drug that directly controls gene expression, bexarotene, could prevent Alzheimer’s disease (AD) pathology in a new mouse model of the disease. We chose to treat an aggressive model of AD, the 5XFAD mice, with bexarotene because these mice lose neurons due to Aβ accumulation which is reflective of human AD pathology. Bexarotene was originally used as anti-cancer agent, but has been shown in our laboratory and others to reduce levels of amyloid beta (Aβ), decrease inflammation, and improve the effectiveness of an important lipid carrier in the brain, ApoE. Two week treatment of bexarotene improved behavioral testing, reduced inflammation, and prevented neuron loss during early and late stages of pathology in the 5XFAD mice. Additionally, bexarotene improved neuron health through reduction in internal accumulations of Aβ and its parent protein, amyloid precursor protein (APP). This was a unique and unexpected finding in the context of bexarotene treatment, and we are continuing to examine new mechanisms of drug action.