Altered metabolic profile in the frontal cortex of PS2APP transgenic mice, monitored throughout their life span.
The transgenic mouse line PS2APP (PS2N141I x APP(swe)) develops an age-related cognitive decline associated with severe amyloidosis, mimicking the pathophysiologic processes in Alzheimer disease (AD). In the quest for biomarkers to monitor, noninvasively, the progression of the disease, we used magnetic resonance imaging and 1H-spectroscopy to characterize PS2APP mice throughout their life span. Morphometric measurements revealed only small size differences to controls. The metabolic profile, however, showed clear indicators of hypometabolism with age in the PS2APP mice: both N-acetyl-aspartate and glutamate were significantly reduced in the older animals. These spectroscopic measures in vivo correlated well with the plaque load in the frontal cortex. A diagnostic test, based on these measures, reached 92% sensitivity and 82% specificity at age 20 months. These noninvasive biomarkers can be exploited in preclinical pharmaceutical research to cope with the high variability in transgenic animal models and to enhance the power of drug efficacy studies.
von Kienlin
Markus
M
F. Hoffmann-La Roche Pharmaceuticals Ltd., CH-4070 Basel, Switzerland. markus.von_kienlin@roche.com
Künnecke
Basil
B
Metzger
Friedrich
F
Steiner
Guido
G
Richards
J Grayson
JG
Ozmen
Laurence
L
Jacobsen
Helmut
H
Loetscher
Hansruedi
H
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D015415:Biomarkers; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053766:Presenilin-2; D013057:Spectrum Analysis
D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D008565:Membrane Proteins; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D001224:Aspartic Acid; D018698:Glutamic Acid; C000179:N-acetylaspartate