Annual Report 2012

Investigations of the Mechanism of Action of TagretinR/Bexarotene on Amyloid Clearance in Transgenic Mouse Models

Funding year(s): 
2012
Funding to date: 
$50,343

Recent studies from the laboratory of Dr. Gary Landreth (Cramer P. et. al (2012) Science 335) have demonstrated that Bexarotene (Targretin), a highly selective, blood-brain barrier-permeant, FDA-approved, RXR agonist for the treatment of cutaneous T-cell lymphoma, can rapidly reduce amyloid plaque burden and rescue behavioral deficits in transgenic mouse models of AD. The proposed mechanism of action is via transcriptional activation of PPARγ:RXR- and LXR:RXR-regulated genes, including ApoE, ABCA1 and ABCG1 expression, that facilitates Aβ clearance and promotes microglial phagocytosis. In support of this proposal, the authors reported that treatment of primary microglia or astrocytes with Bexarotene stimulated the expression of apoE, ABCA1 and ABCG1 and secretion of highly lipidated HDL particles, leading to degradation of soluble Aβ42 in a PPARγ-, LXR-, and apoE-dependent manner.

Most notably, Landreth and colleagues observed the rapid removal of both diffuse and compact Aβ plaques in the cortex and hippocampus of APPswe/PS1DE9 transgenic mice (APP/PS1 mice) after acute treatment with Bexarotene. Targretin or vehicle (H2O) was orally administered in 6-month-old APP/PS1 mice daily for three, seven or 14 days. The authors observed the progressively enhanced expression of apoE, ABCA1 and ABCG1 and elevated HDL levels in both the hippocampus and cortex of Targretin-treated mice, accompanied by a sustained 30 percent reduction in soluble Aβ levels throughout the 14-day treatment period. Insoluble Aβ levels were reduced by 40 percent after 72 hours and progressively decreased over the subsequent 14 days. Total and thioflavin-S+ Aβ plaques were reduced by ~75 percent after seven and 14 days of Bexarotene treatment.

Furthermore, abundant Aβ-laden microglia were observed after three days of Bexarotene treatment, suggesting their involvement in the phagocytic removal of Aβ deposits. To assess whether Targretin could decrease Aβ burden in older animals with greater plaque deposition, 11-month-old APP/PS1 mice were treated with Targretin for seven days and again, there was found significantly reduced levels of soluble and insoluble Aβ40 and Aβ42, a 50 percent reduction in plaque number, and a concurrent increase in expression of apoE, the cholesterol transporters, and HDL levels. Thus, the authors concluded that acute Targretin treatment is efficacious at both early and later stages of pathogenesis in this mouse model.

In view of the significant implications of these landmark findings for the development of novel AD therapeutics, we performed a small pilot study (N=3 each for vehicle and drug) using 8-month-old male APP/PS1 mice that were treated orally with a commercial source of Bexarotene for seven days. We failed to observe any differences in hippocampal or cortical amyloid plaque area or plaque counts between vehicle and bexarotene-treated animals. We confirmed the levels of ABCA1 were elevated in the brains of Bexarotene-treated animals, indicating access of the compound into the CNS. We now propose to extend our preliminary findings by assessing the impact of Targretin on Abeta levels and amyloid pathology in larger cohorts of APP/PS1 and "5X FAD" transgenic mouse models.
 

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