title: Altered brain uptake of therapeutics in a triple transgenic mouse model of Alzheimer's disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The brain uptake of probe compounds was measured in 18-20 month old wild type (WT) and triple transgenic (3×TG) AD mice using an in situ transcardiac perfusion technique. These results were mechanistically correlated with immunohistochemical and molecular studies.
  
  
  RESULTS
  The brain uptake of the paracellular marker, [(14)C] sucrose, did not differ between WT and 3×TG mice. The brain uptake of passively diffusing markers, [(3)H] diazepam and [(3)H] propranolol, decreased 54-60% in 3×TG mice, consistent with a 33.5% increase in the thickness of the cerebrovascular basement membrane in 3×TG mice. Despite a 42.4% reduction in P-gp expression in isolated brain microvessels from a sub-population of 3×TG mice (relative to WT mice), the brain uptake of P-gp substrates ([(3)H] digoxin, [(3)H] loperamide and [(3)H] 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Dharmini C
authors.initials: DC
authors.lastname: Mehta
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Short
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Nicolazzo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D004077:Digoxin / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010599:Pharmacokinetics; D011433:Propranolol / Q000493:pharmacokinetics; D013395:Sucrose / Q000493:pharmacokinetics; D019076:Transgenes; D014665:Vasodilator Agents / Q000493:pharmacokinetics; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014665:Vasodilator Agents; D013395:Sucrose; D004077:Digoxin; D011433:Propranolol; D014700:Verapamil