Apolipoprotein E4 Impairs in vivo Hippocampal Long-Term Synaptic Plasticity by Reducing the Phosphorylation of CaMKIIα and CREB

Article type: Research Article

Authors: Qiao, Feng^a | Gao, Xiu-Ping^b | Yuan, Li^a | Cai, Hong-Yan^a | Qi, Jin-Shun^{a; *}

Affiliations: [a] Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, P.R. China | [b] Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA

Correspondence: [*] Correspondence to: Jin-Shun Qi, PhD, Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China. Tel.: +86 351 413 5091; E-mail: [email protected].

Abstract: 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.

Keywords: Apolipoprotein E4, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), cAMP response element-binding protein (CREB), hippocampus, late-phase long-term potentiation, synaptic plasticity

DOI: 10.3233/JAD-140375

Journal: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1165-1176, 2014