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

Abstract

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 (Abeta) peptide and tau patterns, chaperones and autophagy in WT and AbetaPP{swe} mice. We have found that AbetaPP{swe} 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 Abeta 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.

The sleep–wake Cycle and Alzheimer’s Disease: What do We know?

“…This increase in interstitial space was mimicked with noradrenergic receptor blockade, suggesting that locus coeruleus-derived noradrenergic signaling during wakefulness may be critical for the effect. However, several questions still remain to be determined, including the dynamics of clearance of endogenous Aβ and other proteins, as well as the distinction between sleep and the anesthetized state, which are very different brain states with previously reported contradictory effects on AD pathology [84,85]. …”

Orthopedic Surgery and Post-Operative Cognitive Decline in Idiopathic Parkinson’s Disease: Considerations from a Pilot Study

“…General anesthesia remains an unconfirmed influence on cognitive decline in numerous randomized trials [7–9], despite animal studies suggesting that inhalational anesthetics enhance oligomerization and cytotoxicity of amyloid β peptides (a protein change associated with Alzheimer’s Disease) [10, 11], tau phosphorylation[12], and associated neuroinflammatory responses in humans [13, 14]. Surgery-related mechanisms on post-operative cognitive dysfunction (POCD), most often studied in cardiac populations, remain equally inconclusive.…”

Alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigates isoflurane-induced cognitive impairment in aged rats

“…In contrast to the changes of proinflammatory cytokines, the tendency of increased apoptosis in the hippocampal CA1 region of the rats exposed to 1.3% isoflurane is in agreement with the impaired performance of these rats in the water maze test. Because hippocampal neuronal apoptosis [5,10,11,25], amyloid pathology [26], cholinergic dysfunction [27], and synaptic ultrastructure impairments [5,10,11,28], and so forth were postulated to be associated with isoflurane-induced cognitive dysfunction, the phenomenon may be caused by detrimental effects of isoflurane in the early phase, such as acute neuroinflammation, so that the previously mentioned events subsequently occur and lead to the delayed cognitive dysfunction.…”