Hui Li

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.

Volatile anesthetics and surgery can trigger neuroinflammation and neurological dysfunction, but their long-term effects remain poorly understood. Young adult male and female C57BL/6 mice underwent 4 h of 2% isoflurane anesthesia combined with laparotomy (Iso/OP) or sham treatment. At 12 weeks, olfactory and cognitive functions were assessed, followed by RNA sequencing of olfactory bulbs and hippocampi and plasma extracellular vesicle (EV) profiling. EV-associated inflammatory bioactivity was evaluated by hippocampal injection into naïve male mice. Iso/OP induced olfactory deficits at 12 weeks, with greater impairment in females. Female mice also exhibited deficits in spatial working memory and associative learning, whereas males showed relatively preserved cognitive function. Transcriptomic analyses revealed sex-dependent alterations in pathways related to synaptic function, neurodevelopment, extracellular matrix remodeling, stress responses, and chemotaxis. Iso/OP reduced circulating EV abundance, particularly among 40–100 nm particles, and altered EV proteomic profiles. Exploratory analyses of pooled hippocampal tissues revealed distinct cytokine and chemokine profiles following injection of plasma EVs from the four donor groups. Collectively, these findings demonstrate sex-dependent neurological and molecular alterations persisting 12 weeks after Iso/OP, accompanied by changes in circulating EVs. The exploratory EV transfer findings warrant further investigation into the potential contribution of circulating EVs to brain inflammatory responses.

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis for these effects remain poorly understood. To define age-dependent transcriptional responses, we profiled cardiac gene expression across young adult (3 m), late middle-aged (17 m), and old mice (27 m) following 2 h isoflurane and operative (Iso/Op) exposure. Across all age groups, 24 h after cessation, Iso/Op induced distinct transcriptional signatures relative to the sham, with conserved perturbations in oxidative stress responses, Ca²⁺ handling, hypertrophy-associated signaling, and energy metabolism. In 3 m hearts, transcriptional alterations were characterized by dysregulation of small-molecule catabolism, fatty acid metabolism, endoplasmic reticulum processing, and cytoskeletal organization. In 17 m hearts, lipid metabolic disruption was amplified and accompanied by suppression of muscle system and calcium signaling pathways. In 27 m hearts, Iso/Op robustly activated PPAR and AMPK signaling and fatty acid catabolic programs while downregulating pathways governing contractility, actin organization, and morphogenesis, consistent with age-associated maladaptive metabolic reprogramming. To assess persistence, we analyzed a longitudinal cohort of 20 m mice five weeks after exposure and observed sustained transcriptomic remodeling driven predominantly by isoflurane, including mitochondrial dysfunction and altered expression of genes linked to diabetic cardiomyopathy, extracellular matrix integrity, and neurodegeneration-associated pathways. Together, these data suggest that isoflurane-based perioperative stress can produce age-amplified and durable metabolic and structural cardiac remodeling, implicating impaired lipid utilization and mitochondrial homeostasis as potential mechanisms of long-term cardiovascular vulnerability.

Approximately 20% of all spinal cord injuries (SCI) occur in persons aged 65 years or older. Longitudinal, population-based studies showed that SCI is a risk factor for dementia. However, little research has addressed the potential mechanisms of SCI-mediated neurological impairment in the elderly. We compared young adult and aged C57BL/6 male mice subjected to contusion SCI, using a battery of neurobehavioral tests. Locomotor function showed greater impairment in aged mice, which was correlated with reduced, spared spinal cord white matter and increased lesion volume. At 2 months post-injury, aged mice displayed worse performance in cognitive and depressive-like behavioral tests. Transcriptomic analysis identified activated microglia and dysregulated autophagy as the most significantly altered pathways by both age and injury. Flow cytometry demonstrated increased myeloid and lymphocyte infiltration at both the injury site and brain of aged mice. SCI in aged mice was associated with altered microglial function and dysregulated autophagy involving both microglia and brain neurons. Altered plasma extracellular vesicles (EVs) responses were found in aged mice after acute SCI. EV-microRNA cargos were also significantly altered by aging and injury, which were associated with neuroinflammation and autophagy dysfunction. In cultured microglia, astrocytes, and neurons, plasma EVs from aged SCI mice, at a lower concentration comparable to those of young adult SCI mice, induced the secretion of pro-inflammatory cytokines CXCL2 and IL-6, and increased caspase3 expression. Together, these findings suggest that age alters the EVs pro-inflammatory response to SCI, potentially contributing to worse neuropathological and functional outcomes.

Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients.