Anesthesia with Isoflurane Increases Amyloid Pathology in Mice Models of Alzheimer's Disease

There is a great interest in the environmental and genetic factors which modify the risk of Alzheimer's disease since the manipulation of these factors could help to change the prevalence and natural course of this disease. Among the first group, anesthesia and surgery have been considered as risk enhancers, based mostly on in vitro experiments and epidemiological studies. We have investigated the effects of repetitive anesthesia, twice a week, for 3 months, from 7 to 10 months of age, with isoflurane on survival, behavior, apoptosis in hippocampal cells, amyloid-beta (A beta) peptide and tau patterns, chaperones and autophagy in WT and A beta PPswe mice. We have found that A beta PPswe mice treated with isoflurane have increased mortality, less responsiveness after anesthesia, long lasting reduced exploratory behavior, increased number of TUNEL+ apoptotic cells, and increased ratio of pro-apoptotic proteins in hippocampus, reduced astroglial and increased microglial responses, increased A beta aggregates and high molecular weight peptides, abnormal chaperone responses and reduced autophagy. These effects were not present in WT mice, suggesting that the deleterious impact of isoflurane on behavior, survival, neuronal cell death, and processing of proteins involved in neurodegeneration is restricted to subjects with increased susceptibility but does not affect normal subjects.