Omega-3 Fatty Acids Augment the Actions of Nuclear Receptor Agonists in a Mouse Model of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a highly prevalent disorder for which there are no effective therapies. Accumulation of amyloid ␤ (A␤) 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 A␤ 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 -3 fatty acid docosahexaenoic acid (DHA), in combination with bexarotene, enhances LXR:RXR target gene expression of Abca1 and ApoE, reduces soluble forms of A␤, 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.

Caco-2 Cells for Measuring Intestinal Cholesterol Transport - Possibilities and Limitations

“…The latter was even decreased. This is in contrast to findings in other cell types, such as glial cells, brain-like endothelial cells and macrophages [40,44,73]. In a study investigating the potential of bexarotene in atherosclerosis, the mRNA levels of both NPC1L1 and ABCA1 were found to be reduced in the duodenum and jejunum of bexarotene-treated mice, supporting our findings.…”

“…The finding that bexarotene does not increase the protein expression of this bona fide LXR target gene in Caco-2 cells is in contrast to findings e.g. in glial cells, where bexarotene significantly induces ABCA1 expression [40]. For ABCG5, ABCG8, NPC1L1 and ABCB1 data were inconsistent (data not shown) throughout all conditions tested (detailed discussion in the Discussion section).…”

Aβ Extraction from Murine Brain Homogenates

“…Note: The following protocol has been used to extract Aβ from multiple mouse models of Alzheimer’s disease [please see Cramer et al (2012) and Casali et al (2015)]. The user may need to modify dilutions of the final extracted product depending on the particular application (e.g.…”

Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

“…The combination of ω-3 fatty acid docosahexaenoic acid (DHA) and bexarotene co-administration further reduced AD pathology and aided in amelioration of cognitive deficits through the activation of LXR-RXR pathway in amyloid mouse model [111]. …”