Eckenhoff RG, Johansson JS, Wei H, Carnini A, Kang B, Wei W, Pidikiti R, Keller JM, Eckenhoff MF.
Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity.
Anesthesiology. 2004 Sep;101(3):703-9.
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Waking up demented: New ideas about
anesthesia-induced cognitive impairment
In an intriguing paper just published in Anesthesiology, Eckenhoff et al.
seek an explanation for the commonly observed transitory, and sometimes
persistent, cognitive impairment that is observed following surgeries involving
the use of inhaled anesthetics. This observation, along with results of a
number of studies suggesting, but not proving, a link between surgery and
increased risk of Alzheimer’s and Parkinson’s disease in the elderly, led Eckenhoff
et al. to study whether inhaled anesthetics might have direct effects
on amyloid-β protein (Aβ) self-assembly. To do so, the authors used a combination
of biophysical methods to study peptide assembly. These methods
included turbidity measurements, filtration, electron microscopy, Thioflavin
T (ThT) binding, and size exclusion chromatography. In addition, lactate
dehydrogenase (LDH) assays were done on PC12 cells to assess peptide-mediated
cytotoxicity. The basic experimental design used groups including
anesthetic alone, peptide alone, and mixtures of the two. Anesthetics included
halothane, isoflurane, propofol, and ethanol.
Halothane increased Aβ42 aggregation in a concentration-dependent manner.
This anesthetic also augmented ThT binding during Aβ42 self-assembly.
Electron microscopy of the assemblies present at the termination of these experiments
showed fibrils and protofibrils. Examination of the amount of
peptide filterable through a 100 kDa molecular mass membrane revealed
that halothane-treated Aβ assembly reactions were least filterable, followed
in rank order by isoflurane, propofol, and ethanol. Halothane also facilitated
the formation of high molecular weight assemblies, as assessed by size
exclusion chromatography. In addition, halothane, as well as isoflurane, potentiated
the toxic effect of Aβ42 on PC12 cells.
The authors conclude that inhaled anesthetics enhance oligomerization
and cytotoxicity of Alzheimer's disease-associated peptides, and that this effect
may underlie the clinically observed surgery (anesthetic)-associated cognitive
impairment often observed in the elderly. This is an intriguing notion worthy
of further study.
How can the suggestive work of Eckenhoff et al. be placed on a rigorous
experimental foundation? As with any structure-activity study of Aβ, the
key requirement will be determination of the distribution of Aβ assemblies
and a correlation of that distribution with a specific peptide-associated behavior,
whether that behavior is biophysical (filterability, morphology, dye
binding, turbidity) or biological (cytotoxicity). The method of peptide preparation
used here (DMSO solubilization and dissolution into buffer) produces
a heterogeneous population of assemblies, complicating data interpretation.
In particular, although the role of oligomers was discussed explicitly, the
presence of protofibrils and fibrils in the peptide preparations used precludes
determination of the effects of anesthetics on oligomer formation and activity.
Eckenhoff et al. may be right. However, greater confidence in the conclusions
will come through examination of oligomer-specific assembly processes
and effects. The application of more sophisticated spectroscopic methods
to monitor directly anesthetic-peptide interactions would provide additional
support for the authors’ postulations that hydrophobic interactions are central
to the effects observed.