Impaired hypoxic tolerance and altered protein binding of NADH in presymptomatic APP23 transgenic mice.
It is being discussed whether impairment of energy metabolism is a final common pathway of neurodegeneration or initiates the neurodegenerative cascade. The goal was to investigate hypoxic tolerance and oxidative energy metabolism in 4-month-old, presymptomatic B6-Tg(ThylAPP)23Sdz (APP23) mice, a transgenic mouse model of Alzheimer's disease. Posthypoxic recovery of the population spike amplitude in hippocampal region CA1 upon stimulation of Schaffer collaterals in region CA3 (15 min hypoxia, 45 min recovery) was 43+/-46% (mean+/-S.D.) vs. 19+/-35% (P<0.05) in slices from wild-type and transgenic animals, respectively. Fluorescence lifetime sensitive spectroscopy of NADH in the CA1 pyramidal cell layer (gate set for detection of protein-bound NADH) showed a wavelength maximum at 455.3+/-1.6 nm (mean+/-S.D.) in controls and 453.5+/-2.4 nm (P<0.05) in mutants. We conclude that hypoxic tolerance is impaired in presymptomatic APP23 mice and occurs prior to extracellular deposition of amyloid plaques. Impaired energy metabolism may thus partake in initiating the neurodegenerative cascade in a transgenic model of Alzheimer's disease. The blue shift of the spectrum of NADH in mutant mice indicates an altered protein microenvironment of energy metabolism under control conditions.
Department of Neurology, University of Ulm, Steinhövelstrasse 1, 89075 Ulm, Germany.
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M
Büchner
R
R
Huber
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C
Sturchler-Pierrat
M
M
Staufenbiel
M W
MW
Riepe
D000200:Action Potentials / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009243:NAD / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology; D011485:Protein Binding / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics; D013057:Spectrum Analysis
D016564:Amyloid beta-Protein Precursor; D009574:Nitro Compounds; D011422:Propionates; D009243:NAD; C015392:3-nitropropionic acid