Isoflurane and Surgery Aggravate APOE4-Dependent Lipid Dysregulation, Neural Dysfunction, and Neurological Impairment in Male Mice
7 affiliations
- 1Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA
- 2Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
- 3Center for Neurological Disease Research, University of Georgia College of Veterinary Medicine, Athens, GA 30602, USA
- 4Department of Physiology and Pharmacology, University of Georgia College of Veterinary Medicine, Athens, GA 30602, USA
- 5Department of Biomedical Sciences, University of Georgia College of Veterinary Medicine, Athens, GA 30602, USA
- 6Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- 7University of Maryland-Medicine Institute for Neuroscience Discovery (UM-MIND), University of Maryland School of Medicine, Baltimore, MD 21201, USA
Abstract
Perioperative exposure to the volatile anesthetic isoflurane (ISO) during surgery (OP) has been associated with cognitive and olfactory deficits and may increase the risk of Alzheimer’s disease (AD). Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, contributes to disease pathogenesis through disrupted lipid homeostasis. However, whether ISO/OP interacts with APOE genotype to influence neurological vulnerability remains unclear. Young adult, presymptomatic humanized APOE4 and APOE3 knock-in mice underwent laparotomy under 2 h of ISO anesthesia. Microglia and astrocytes were isolated from the olfactory bulb (OB) and hippocampus (HI) for lipidomic profiling. Awake in vivo OB recordings assessed neuronal excitability and network activity, while ex vivo patch-clamp recordings assessed synaptic transmission in the OB and HI. On day 7, APOE4/ISO/OP glia showed greater lipid perturbations than APOE3/ISO/OP glia. In vivo recordings revealed genotype-dependent alterations in OB excitability and network operation, while patch-clamp recordings identified altered excitatory and inhibitory synaptic transmission in the OB and HI. APOE4/ISO/OP mice exhibited persistent odor memory deficits, transient olfactory sensitivity loss, early motor impairment, and delayed cognitive dysfunction. OB RNA sequencing identified alterations in calcium transport and metabolic pathways in APOE4 male mice at 90 days following exposure. Together, these findings demonstrate APOE4-dependent vulnerability to ISO/OP, characterized by glial lipid dysregulation, neural circuit dysfunction, and neurological impairment, and support a potential mechanistic contribution of altered lipid homeostasis.
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BibTeX
@article{li2026isoflurane,
title = {{Isoflurane and Surgery Aggravate APOE4-Dependent Lipid Dysregulation, Neural Dysfunction, and Neurological Impairment in Male Mice}},
author = {Yun Li and Yuanyuan Ji and Cosar Uzun and Syed Taufiqul Islam and Meigeng Hu and Dan Zhao and Yaping Li and Hangnoh Lee and Zihui Wang and Hui Li and Jace W. Jones and Shaolin Liu and Junfang Wu},
journal = {Cells},
year = {2026},
month = nov,
doi = {10.3390/cells15212038},
url = {https://www.mdpi.com/2073-4409/15/21/2038},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Isoflurane and Surgery Aggravate APOE4-Dependent Lipid Dysregulation, Neural Dysfunction, and Neurological Impairment in Male Mice
AU - Yun Li
AU - Yuanyuan Ji
AU - Cosar Uzun
AU - Syed Taufiqul Islam
AU - Meigeng Hu
AU - Dan Zhao
AU - Yaping Li
AU - Hangnoh Lee
AU - Zihui Wang
AU - Hui Li
AU - Jace W. Jones
AU - Shaolin Liu
AU - Junfang Wu
PY - 2026
DA - 2026/11/09
JO - Cells
DO - 10.3390/cells15212038
UR - https://www.mdpi.com/2073-4409/15/21/2038
AB - Perioperative exposure to the volatile anesthetic isoflurane (ISO) during surgery (OP) has been associated with cognitive and olfactory deficits and may increase the risk of Alzheimer’s disease (AD). Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, contributes to disease pathogenesis through disrupted lipid homeostasis. However, whether ISO/OP interacts with APOE genotype to influence neurological vulnerability remains unclear. Young adult, presymptomatic humanized APOE4 and APOE3 knock-in mice underwent laparotomy under 2 h of ISO anesthesia. Microglia and astrocytes were isolated from the olfactory bulb (OB) and hippocampus (HI) for lipidomic profiling. Awake in vivo OB recordings assessed neuronal excitability and network activity, while ex vivo patch-clamp recordings assessed synaptic transmission in the OB and HI. On day 7, APOE4/ISO/OP glia showed greater lipid perturbations than APOE3/ISO/OP glia. In vivo recordings revealed genotype-dependent alterations in OB excitability and network operation, while patch-clamp recordings identified altered excitatory and inhibitory synaptic transmission in the OB and HI. APOE4/ISO/OP mice exhibited persistent odor memory deficits, transient olfactory sensitivity loss, early motor impairment, and delayed cognitive dysfunction. OB RNA sequencing identified alterations in calcium transport and metabolic pathways in APOE4 male mice at 90 days following exposure. Together, these findings demonstrate APOE4-dependent vulnerability to ISO/OP, characterized by glial lipid dysregulation, neural circuit dysfunction, and neurological impairment, and support a potential mechanistic contribution of altered lipid homeostasis.
SN - 2073-4409
ER -