Alzheimer's disease (AD) is a highly prevalent disorder for which there are no effective
therapies. Accumulation of
amyloid β (Aβ)
peptides in the brain is associated with impaired cognition and memory, pronounced inflammatory dysregulation, and subsequent
amyloid plaque deposition. Thus, drugs that promote the clearance of Aβ
peptides and resolution of
inflammation may represent viable therapeutic approaches. Agonists of
nuclear receptors LXR:RXR and
PPAR:RXR act to ameliorate AD-related
cognitive impairment and
amyloid accumulation in murine models of AD. The use of an agonist to the
nuclear receptor RXR,
bexarotene, as monotherapy against AD, presents potential challenges due to the metabolic perturbations it induces in the periphery, most prominently
hypertriglyceridemia. We report that the ω-3
fatty acid docosahexaenoic acid (DHA), in combination with
bexarotene, enhances LXR:RXR target gene expression of Abca1 and
ApoE, reduces soluble forms of Aβ, and abrogates release of pro-inflammatory
cytokines and mediators both in vitro and in a mouse model of AD. Moreover, DHA abrogates
bexarotene-induced
hypertriglyceridemia in vivo. Importantly, dual
therapy promotes reductions in AD pathology and resultant amelioration of cognitive deficits. While monotherapy with either
bexarotene or DHA resulted in modest effects in vitro and in vivo, combined treatment with both agents produced a significant additive benefit on associated AD-related phenotypes, suggesting that targeted combinatorial agents may be beneficial over single agents alone in treating AD.