A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo.
Although amyloid beta (Abeta) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD), their contribution to other pathological features of AD remains unclear. To address the latter, we generated APP transgenic mice expressing the E693Delta mutation, which causes AD by enhanced Abeta oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal Abeta oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that Abeta oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are a useful model of Abeta oligomer-induced pathology in the absence of amyloid plaques.
Tomiyama
Takami
T
Departments of Neuroscience, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. tomi@med.osaka-cu.ac.jp
Matsuyama
Shogo
S
Iso
Hiroyuki
H
Umeda
Tomohiro
T
Takuma
Hiroshi
H
Ohnishi
Kiyouhisa
K
Ishibashi
Kenichi
K
Teraoka
Rie
R
Sakama
Naomi
N
Yamashita
Takenari
T
Nishitsuji
Kazuchika
K
Ito
Kazuhiro
K
Shimada
Hiroyuki
H
Lambert
Mary P
MP
Klein
William L
WL
Mori
Hiroshi
H
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins