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.
Highlights
The principle pathological characteristics of Alzheimer’s disease (AD) include the extracellular deposition of βamyloid (Aβ) plaques and intracellular aggregation of tau in the brain, abnormal synaptic function, and chronic inflammatory responses in neural tissue
Gender-related differences are important in the evaluation of any retinoid X receptors (RXRs) agonist or other compounds influencing this pathway because ApoE function can be modified by gender [19,20]
We analyzed the effects of treatment on ABCA1 levels in APPswe/PS1ΔE9 mice, and found that the use of DMSO or corn oil as a vehicle does not create a significant difference in the relative means of bexarotene treated groups normalized to their respective vehicle [(M=1.570, SD=0.203) and (M=1.641, SD=0.157), respectively F(1,10)=0.044, p=0.837], and that there was no interaction between vehicle used and treatment group
Summary
The principle pathological characteristics of Alzheimer’s disease (AD) include the extracellular deposition of βamyloid (Aβ) plaques and intracellular aggregation of tau in the brain, abnormal synaptic function, and chronic inflammatory responses in neural tissue. Cramer et al [13] conducted studies with bexarotene in transgenic mouse models of Aβ amyloidosis. They reported that acute treatment with bexarotene upregulated ABCA1 and ApoE, rapidly reduced the Aβ plaque burden in the brain, and ameliorated cognitive deficits in these models. Several groups have failed to replicate the effect of bexarotene on Aβ plaque burden in these and other related mouse models, despite achieving upregulation of the proposed targets ApoE and ABCA1 [14,15,16,17]. 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. Recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial
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