Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice

Abstract

BackgroundThough the precise cause(s) of Alzheimer’s disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial.FindingsIn efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice.ConclusionsWe recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy.

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

“…Whereas some studies report a decrease in soluble forms of brain A␤ peptides [17,18,23], other studies failed to observe an effect [20,21,50,51]. Behavioral studies of bexarotene-treated AD animals have either reported no improvement [19,21,50,51] Fig. 5.…”

“…Furthermore, bexarotene induces microglial and astrocyte-mediated clearance of A␤ peptides, although the corresponding cellular and molecular mechanisms have yet to be characterized in detail [17]. Several research groups have tried to reproduce Cramer's initial study in various different AD models, with disparate results [18][19][20][21][22][23]. Therefore the link between bexarotene, ApoE, ABCA1, and AD could be of potential therapeutic value, although further investigation of the underlying cellular and molecular mechanisms is required [24].…”

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

“…Recently, Cramer et al [16] reported that the RXR-selective agonist bexarotene enhanced apolipoprotein E-dependent A␤ clearance from the brain and improved behavioral deficits in A␤PP/PS1 mice. However, there are conflicting data regarding the therapeutic effect of bexarotene on A␤PP mice [18][19][20][21][22]. Furthermore, it remains unclear whether coactivation of RARs with RXRs is required to improve AD pathology and memory deficits.…”

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

“…Indeed, Bex increased mouse (m)-apoE levels, decreased soluble A␤ within hours, and reduced insoluble A␤ after 3 days in transgenic mouse models expressing familial AD mutations (FAD-Tg) (11). However, recent data in multiple FAD-Tg models, although variable (12), demonstrate that Bex has no effect on insoluble A␤, but may lower soluble A␤42 and soluble oA␤ levels (13)(14)(15)(16). In addition, these recent studies indicate that rather than increasing APOE (gene coding for apolipoprotein E) expression, Bex may lower soluble A␤ through increasing the levels of other RXR target proteins, specifically, the ATP-binding cassette transporters (ABC) ABCA1 and ABCG1 (13)(14)(15)(16).…”

“…In APOE-TR mice, which do not express h-A␤, Bex reverses the lipidation deficiency of APOE4 (35). Given the conflicting data on Bex treatment in FAD-Tg mice expressing m-apoE (12), it is vital, from a translational perspective, to further dissect the interactive effects of h-APOE and RXR agonists on A␤ accumulation in an in vivo model that expresses h-APOE.…”