Isoflurane in the Aged Brain: A Link to Altered Amyloid Precursor Protein Processing

General anaesthesia can cause an altered mental status, particularly in elderly patients. While these changes usually represent a temporary, reversible delirium, there is growing, but still inconclusive evidence that suggests isoflurane can induce changes to key neurodegenerative proteins such as the amyloid precursor protein and its processed fragment, amyloid beta peptide. To further characterize the conditions under which such changes may take place, we have undertaken a preliminary study in which 17-month-old C57/Bl6 mice were exposed to two anaesthetic regimens. One cohort was treated with 1% isoflurane for 6 hours (acute); the second cohort was treated with 1.4% isoflurane for 2 hours per day for five consecutive days (chronic). Brain homogenates were analysed by western blotting. An acute exposure significantly altered processing of full-length amyloid precursor protein with a reduction in its soluble levels (-22%, p< 0.05), while there was a concomitant increase in levels of its processed fragments; 81% (p< 0.05) for a 60 kDa fragment and 32% (p< 0.05) for a 40 kDa fragment. There were fewer effects from a chronic exposure, with membrane levels of amyloid precursor protein decreasing (-17%, p< 0.05). These findings suggest that an acute exposure to isoflurane can lead to in vivo changes to key pathways involved in the development of Alzheimer's disease.