Abstract
Alzheimer's disease (AD) is a multifaceted disease with different pathological features. Retinoid X receptor (RXR) is a nuclear receptor that can be activated by 9‐cis retionoic acid. RXR agonists are emerging as a new class of agents capable of promoting Aβ clearance by enhancing expression of ApoE that traffics Aβ. IRX4204 is a rexinoid agonist with high potency and selectivity to RXRs and an extensive history of safety in oncology clinical trials. In this study, we tested the effect of IRX4204 on amyloid‐mediated neuropathology and cognitive impairments in an animal model of AD. We found that IRX4204 can effectively pass the blood brain barrier and accumulate in the brain at a concentration sufficient to activate the CREB signaling pathway in vitro. IRX4204 can interfere with Aβ and tau oligomerization, promote ApoE protein expression, and improve synaptic plasticity. Moreover, in vivo IRX4204 treatment can significantly improve cognitive function and reduce neuropathology in TgCRND8 mouse model of AD. Our study demonstrated IRX4204 can be potentially developed into a disease‐modifying agent and provided impetus for immediate testing of IRX4204 in clinical settings for AD prevention and treatment.
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