Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia

Abstract

Background Anesthesia induces Tau phosphorylation and cognitive impairment in young, but not adult, mice. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its toxic fragments are reported to induce neurodegeneration and neurocognitive impairment in patients with Alzheimer's disease (AD). Therefore, we set out to test the hypothesis that the difference in ApoE fragments, but not the full‐length ApoE, contributes to the difference in Tau phosphorylation and neurocognitive functions following sevoflurane anesthesia in young mice. Methods Sevoflurane was administered to wild‐type (WT), ApoE‐knockout (ApoE‐KO), ApoE3‐targeted replacement (ApoE3 expresses both full‐length and fragmented ApoE), and ApoE2‐targeted replacement (ApoE2 only expresses full‐length ApoE) mice. The mRNA and protein levels of ApoE, phosphorylated Tau (pTau), and cognitive function were tested in the mice. Results Sevoflurane anesthesia enhanced ApoE mRNA, total ApoE, full‐length ApoE, ApoE fragments, Tau phosphorylation (AT8 and PHF1), and cognitive impairment in young mice, but not in adult mice. ApoE2, but not ApoE3 or ApoE‐KO, mice showed reduced sevoflurane‐induced pTau elevation and cognitive impairment. Conclusion These data suggest that elevated ApoE fragments rather than full‐length ApoE might be one of the underlying mechanisms of age‐dependent Tau phosphorylation and cognitive impairment in young mice following sevoflurane anesthesia.

Tandem mass tag-based quantitative proteomic analysis of effects of multiple sevoflurane exposures on the cerebral cortex of neonatal and adult mice

“…Based on previous research (7)(8)(9)(10)(11), we discovered that newborn mice exhibit neurotoxicity after multiple exposures to sevoflurane anesthesia. In the current study, we employed quantitative proteomic analysis using TMTpro(16-plek) tagging and LC-MS/MS to identify 443 DEPs.…”

“…It has been reported that repeated or long-term sevoflurane exposure prior to 3-4 years of age can increase the potential for future learning and memory challenges (3)(4)(5), although available data remain debatable (6). Furthermore, our previous studies have demonstrated that multiple exposures to inhalational anesthetics, such as sevoflurane, can cause adverse effects, including neuroinflammation, apoptosis, synaptic insufficiency, and cognitive deficits in 6-day-old newborn mice, while 60-day-old adult mice showed no notable damage (7)(8)(9)(10)(11). The mechanisms underlying these age-dependent effects remain elusive.…”

Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases

“…The role of this apoE truncated fragment to enhance tau phosphorylation was documented by studies showing that transgenic expression of apoE(Δ272–299) in mice caused tau hyperphosphorylation, preneurofibrillary tangle formation, learning and memory impairment, and early death [ 158 ]. Moreover, this C-terminal truncated apoE fragment was not detected in mice expressing apoE2, where tau phosphorylation and cognitive impairment were also found to be reduced [ 159 ]. Whether differences in susceptibility of apoE2 and apoE4 to intraneuronal proteolysis is due to conformational differences (as reviewed above in Section 2.1.1 ) need to be clarified.…”

Research progress on molecular mechanisms of general anesthetic-induced neurotoxicity and cognitive impairment in the developing brain

“…In addition, Tau is a microtubule-associated protein, and the hyperphosphorylated form of Tau is significantly increased after nerve injury ( 60 ), so it is considered to be an important factor affecting general anesthetics leading to neurotoxicity and cognitive impairment in the newborn brain. ApoE toxic fragment may be one of the potential mechanisms of neuronal Tau phosphorylation in neonatal mice exposed to sevoflurane ( 61 ). Coenzyme Q10 may reduce ApoE and phosphorylated Tau expression, thereby attenuating sevoflurane-induced neuroinflammation in mouse hippocampal neurons of newborn mice ( 62 ).…”