Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB.

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.