Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB.
Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+/calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4.
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, P.R. China.
Feng
F
Qiao
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
Xiu-Ping
XP
Gao
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, P.R. China.
Li
L
Yuan
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, P.R. China.
Hong-Yan
HY
Cai
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, P.R. China.
Jin-Shun
JS
Qi
D000704:Analysis of Variance; D000818:Animals; D053327:Apolipoprotein E4 / Q000494:pharmacology*; D001703:Biophysics; D050882:CREB-Binding Protein / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D053327:Apolipoprotein E4; D013912:Threonine; D012694:Serine; D050882:CREB-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
Apolipoprotein E4; Ca$^{2+}$/calmodulin-dependent protein kinase II (CaMKII); cAMP response element-binding protein (CREB); hippocampus; late-phase long-term potentiation; synaptic plasticity