Age-dependent enhancement of hippocampal long-term potentiation in knock-in mice expressing human apolipoprotein E4 instead of mouse apolipoprotein E.
Human apolipoprotein E (apoE) comprises three isoforms, apoE2, apoE3 and apoE4, and apoE4 has been reported as a risk factor of Alzheimer's disease (AD). One of the clinical symptoms of AD is disorder of memory that has been suggested to be related with synaptic plasticity such as long-term potentiation (LTP). Here, we show the enhancement of hippocampal LTP at younger age in knock-in mice lacking mouse apoE, but instead expressing human apoE4. The enhancement of LTP in apoE4 knock-in mice is age-dependent, and it disappears in adult apoE4 knock-in mice. In apoE3 knock-in mice LTP is unaltered, thus human apoE4, but not apoE3, specifically modulates synaptic plasticity at younger age. Since basal synaptic transmission and distribution of glutamate receptors, as well as presynaptic functions, are intact in apoE4 knock-in mice, postsynaptic functional modification of LTP through lipid homeostasis is suggested. ApoE4 knock-in mice would be a useful animal model of human apoE4 carriers, and our finding that LTP is enhanced in younger apoE4 knock-in mice is in accord with the previous report showing higher intelligence in young human apoE4 carriers.
Laboratory for Neurodegeneration Signal, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Hiroyuki W
HW
Kitamura
Hiroki
H
Hamanaka
Masahiko
M
Watanabe
Koji
K
Wada
Chiharu
C
Yamazaki
Shinobu C
SC
Fujita
Toshiya
T
Manabe
Nobuyuki
N
Nukina
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate