Brain metabolite clearance: impact on Alzheimer’s disease

Alzheimer’s Disease (AD) is a complex neurodegenerative disorder often associated with aging and characterized by several critical molecular changes that take place in the brain. Among the molecular hallmarks of AD, increased levels of amyloid β-peptide (Aβ) and the subsequent Aβ-derived damage are the most well-studied factors; however, despite the large amounts of effort and resources devoted to the study of AD and AD pathophysiology, the scientific community still awaits therapeutic alternatives capable of ensuring a better outcome for AD patients. In 2012, Cramer et al. (Science 335:1503-1506 2012) astonished the scientific community by rescuing behavioral and cognitive impairments in AD mouse models via oral administration of bexarotene, a drug used to treat some types of skin cancer. Moreover, these authors demonstrated that bexarotene, a retinoid X receptor (RXR) agonist, exerts major effects on Aβ levels, mainly through increased apolipoprotein E (ApoE) expression. Apart from the valid questions addressed in Cramer’s work, only a few attempts have been made to explain the effects of bexarotene. Most of these explanations have been solely based on the ability of bexarotene to reduce Aβ levels and not on the mechanisms that lead to such a reduction. Although it is well known that an imbalance in the Aβ production/excretion rate is the basis of increased Aβ levels in AD, no further explanations have been proposed to address the potential involvement of the blood-brain barrier (BBB), a critical Aβ-clearance structure, in the bexarotene-mediated effects. Moreover, no attempt has been made to explain how the different effects observed after bexarotene administration are connected to each other. Based on current information and on our own experience with nuclear receptors (NR), we offer new perspectives on the mechanisms of bexarotene action, which should help to improve our knowledge of NRs.