Altered Brain Uptake of Therapeutics in a Triple Transgenic Mouse Model of Alzheimer's Disease

The purpose of this study was to systematically assess the impact of Alzheimer's disease (AD)-associated blood-brain barrier (BBB) alterations on the uptake of therapeutics into the brain. The brain uptake of probe compounds was measured in 18-20 month old wild type (WT) and triple transgenic (3xTG) AD mice using an in situ transcardiac perfusion technique. These results were mechanistically correlated with immunohistochemical and molecular studies. The brain uptake of the paracellular marker, [C-14] sucrose, did not differ between WT and 3xTG mice. The brain uptake of passively diffusing markers, [H-3] diazepam and [H-3] propranolol, decreased 54-60% in 3xTG mice, consistent with a 33.5% increase in the thickness of the cerebrovascular basement membrane in 3xTG mice. Despite a 42.4% reduction in P-gp expression in isolated brain microvessels from a sub-population of 3xTG mice (relative to WT mice), the brain uptake of P-gp substrates ([H-3] digoxin, [H-3] loperamide and [H-3] verapamil) was not different between genotypes, likely due to a compensatory thickening in the cerebrovascular basement membrane counteracting any reduced efflux of these lipophilic substrates. These studies systematically assessed the impact of AD on BBB drug transport in a relevant animal model, and have demonstrated a reduction in the brain uptake of passively-absorbed molecules in this mouse model of AD.