The role of apolipoprotein E4 on calcium homeostasis in primary hippocampal neurons: an in vitro study

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Background We previously demonstrated that apolipoprotein E (apoE4) accelerates neurodegeneration in a transgenic mouse model, but the mechanism is still unclear. A previous study reported that death-associated protein kinase 1 (DAPK1) interacts with the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor, this DAPK1–NR2B interaction increases calcium intake in cells, leading to cell damage. As apoE4 is the strongest genetic risk factor for sporadic Alzheimer’s disease (sAD) and calcium dyshomeostasis is a key driver of sAD-related neurotoxicity, the unclear mechanism linking apoE4 to calcium imbalance remains a critical gap in developing targeted therapies for sAD. Addressing this gap is urgent to advance our understanding of sAD pathogenesis and identify new therapeutic targets. Our study aimed to determine whether the neurotoxic effects of apoE4 are mediated by the interaction between DAPK-1 and the NMDA receptor NR2B subunit. Methods Primary mouse hippocampal neurons were cultured with apoEs in the presence or absence of an NMDA receptor antagonist that preferentially targets NR2B-containing receptors. Intracellular calcium concentration, cell viability and the proteins related to calcium homeostasis were detected. Results Cells treated with apoE4 showed increased levels of intracellular calcium and cell death. The expression of DAPK-1 and NR2B was up-regulated, and interacted with each other under the condition of ApoE4 culture. Conclusion Our study showed that apoE4 causes neurotoxicity by increasing intracellular calcium concentration. The possible mechanism of which was that apoE4 increased the expression of DAPK-1/NMDAR2B, and further promoted the interaction between the two. These results may provide new targets and ideas for the treatment of AD.

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