Neurotoxic 18-kDa apolipoprotein E fragment production contributes to anesthetic sevoflurane-induced tau phosphorylation and neuroinflammation in vitro

Anesthesia may induce neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its 18-kDa fragments are reported to induce neurodegeneration and neuroinflammation in Alzheimer's disease patients. We aimed to test the hypothesis that differences in 18-kDa ApoE fragment levels, but not full-length ApoE, in primary neurons contribute to differences in tau phosphorylation and neuroinflammation with or without sevoflurane administration. Neurons extracted from wild-type (WT), ApoE knockout (ApoE-KO), and ApoE epsilon 3-and epsilon 2-targeted replacement (ApoE epsilon 3, ApoE epsilon 2) mice were divided into control and sevoflurane groups. Neurons in the sevoflurane group were treated with 21% O-2, 5% CO2, and 4.1% sevoflurane, whereas those in the control group were treated with 21% O-2 and 5% CO2 only on day 5 of neuronal culture. ApoE mRNA, full-length ApoE, 18-kDa ApoE fragments, Tau-PS202/PT205 (AT8), Tau-PSer396/404 (PHF1), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 and IL-1 beta levels were measured. The data showed that sevoflurane-induced AT8 and PHF1 increases, and TNF-alpha, IL-6, and IL-1 beta increases in WT or ApoE epsilon 3 neurons (both expressing full-length and 18-kDa fragmented ApoE) could be mitigated in ApoE epsilon 2 (only expressing full-length ApoE), but not in ApoE-KO neurons, indicating that differences in 18-kDa ApoE fragments, but not full-length ApoE, in primary mouse neurons contributed to differences in tau phosphorylation and neuroinflammation with or without 4.1% sevoflurane administration.

Automated summary

Anesthesia may cause neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) has a protective role in neuronal activity and injury repair, while its 18-kDa fragments can induce neurodegeneration and neuroinflammation. This study suggests that the presence of 18-kDa ApoE fragments in primary mouse neurons is associated with differences in tau phosphorylation and neuroinflammation.