Zihui Wang

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.

Schwann cells (SCs) are myelinating cells that promote peripheral nerve regeneration. When nerve lesions form, SCs are destroyed, ultimately hindering nerve repair. The difficulty in treating nerve repair is exacerbated due to SC’s limited and slow expansion capacity. Therapeutic use of adipose-derived stem cells (ASCs) is emerging in combating peripheral nerve injury due to these cells’ SC differentiation capability and can be harvested easily in large numbers. Despite ASC’s therapeutic potential, their transdifferentiation period typically takes more than two weeks. In this study, we demonstrate that metabolic glycoengineering (MGE) technology enhances ASC differentiation into SCs. Specifically, the sugar analog Ac₅ManNTProp (TProp), which modulates cell surface sialylation, significantly improved ASC differentiation with upregulated SC protein S100β and p75NGFR expression and elevated the neurotrophic factors nerve growth factor beta (NGFβ) and glial cell-line-derived neurotrophic factor (GDNF). TProp treatment remarkably reduced the SC transdifferentiation period from about two weeks to two days in vitro, which has the potential to improve neuronal regeneration and facilitate future use of ASCs in regenerative medicine.