Response to comments on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"

Abstract

The data reported in the Technical Comments by Fitz et al., Price et al., Tesseur et al., and Veeraraghavalu et al. replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble β-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer's disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.

Fig. 1. Bexarotene pharmacokinetics

Mice (C57BL/6) were orally gavaged with bexarotene (Targretin) suspended in water and delivered at a final dose of 100 mg/kg. The brains were collected at the indicated intervals between 0 and 8 hours and were then homogenized in phosphate-buffered saline (PBS) (2:1, PBS:brain by weight). Bexarotene and an internal standard were extracted from plasma (open square) or brain (open circle) homogenate by protein precipitation and processed for liquid chromatography–tandem mass spectrometry analysis. The kinetic analysis of bexarotene levels in plasma and brain is shown in (A) and tabulated in (B). Elimination half-life values for plasma and brain were similar and were also similar between dose groups. Within each dose level, exposure (C_max and AUC_0-∞) was similar between plasma and brain. Plasma and brain exposure (C_max and AUC_0-∞) increased in a linear manner with increasing dose. The 4-fold increase in dose from 25 to 100 mg/kg, C_max increased 4.2-fold for plasma and 4.8-fold for brain, and AUC_0-∞ increased 3.7-fold for plasma and 3.4-fold for brain.