Effects of Apolipoprotein E on N-Methyl-D-Aspartate Receptor Signalling: The Roles of Ageing and Chicken Extract

Abstract

Apolipoprotein E4 (apoE4) carriers are more susceptible to cognitive decline during ageing, but the underlying mechanisms are unclear. We investigated the relationship between N-methyl-D-aspartate receptor (NMDAR), a learning and memory receptor, and apoE4 in human apoE-knockin (apoE-KI) mice at different ages. ApoE4 downregulates phosphorylation and expression of NMDAR subunits in hippocampal CA3 and cortex at old age, which correlated with increasing neuronal apoE4 production. Downregulation of NMDAR-associated protein, postsynaptic density protein PSD95 and apoE receptor, LRP1, in apoE4-KI mice at all ages suggests alterations in synaptic integrity. The phosphorylation of NMDAR-induced kinases including aCaMKII, PKCa, ERK and CREB are reduced in old apoE4-KI mice which could contribute to learning deficits. Chicken extract (CE) is taken as a mental health supplement and we examined its potential in triggering learning and memory pathways in human ApoE (huApoE)-transfected neurons. PKA-Ca pathway was downregulated whilst PKCa pathway was upregulated in CE-treated apoE4 and apoE3 neurons respectively. The basal levels of intracellular Ca2+, aCaMKII and GluR1 S831 were increased in apoE3 neurons, as opposed to mock and apoE4-transfected neurons after treatment. CE may help to enhance NMDAR-coupled pathways in apoE3 but not in apoE4 neurons.