Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor protein.
Previous studies suggested that cleavage of the amyloid precursor protein (APP) at aspartate residue 664 by caspases may play a key role in the pathogenesis of Alzheimer's disease. Mutation of this site (D664A) prevents caspase cleavage and the generation of the C-terminal APP fragments C31 and Jcasp, which have been proposed to mediate amyloid-beta (Abeta) neurotoxicity. Here we compared human APP transgenic mice with (B254) and without (J20) the D664A mutation in a battery of tests. Before Abeta deposition, hAPP-B254 and hAPP-J20 mice had comparable hippocampal levels of Abeta(1-42). At 2-3 or 5-7 months of age, hAPP-B254 and hAPP-J20 mice had similar abnormalities relative to nontransgenic mice in spatial and nonspatial learning and memory, elevated plus maze performance, electrophysiological measures of synaptic transmission and plasticity, and levels of synaptic activity-related proteins. Thus, caspase cleavage of APP at position D664 and generation of C31 do not play a critical role in the development of these abnormalities.
Harris
Julie A
JA
Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, California 94158, USA.
Devidze
Nino
N
Halabisky
Brian
B
Lo
Iris
I
Thwin
Myo T
MT
Yu
Gui-Qiu
GQ
Bredesen
Dale E
DE
Masliah
Eliezer
E
Mucke
Lennart
L
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011597:Psychomotor Performance / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D020169:Caspases