Compromised hemodynamic response in amyloid precursor protein transgenic mice.
APP23 transgenic mice overexpressing amyloid precursor protein (APP751) reproduce neuropathological changes associated with Alzheimer's disease such as high levels of amyloid plaques, cerebral amyloid angiopathy, and associated vascular pathologies. Functional magnetic resonance imaging (fMRI) was applied to characterize brain functionality in these mice through global pharmacological stimulation. The cerebral hemodynamic response to infusion of the GABA(A) antagonist bicuculline was significantly reduced in aged APP23 mice compared with age-matched wild-type littermates. This is in part attributable to a compromised cerebrovascular reactivity, as revealed by the reduced responsiveness to vasodilatory stimulation by acetazolamide. The study shows that fMRI is a sensitive tool to phenotype genetically engineered animals modeling neuropathologies.
Mueggler
Thomas
T
Central Technologies, Novartis Pharma, AG, CH-4002 Basel, Switzerland.
Sturchler-Pierrat
Christine
C
Baumann
Diana
D
Rausch
Martin
M
Staufenbiel
Matthias
M
Rudin
Markus
M
D000086:Acetazolamide / Q000494:pharmacology; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001835:Body Weight; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
D016564:Amyloid beta-Protein Precursor; D002257:Carbonic Anhydrase Inhibitors; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D000086:Acetazolamide; D001640:Bicuculline