Propofol and Thiopental Suppress Amyloid Fibril Formation and GM1 Ganglioside Expression through the γ-Aminobutyric Acid A Receptor

Abstract Background: The incidence of Alzheimer disease may increase after surgical interventions. Amyloid β-protein (Aβ) fibrillogenesis, which is closely related to Alzheimer disease, is reportedly accelerated by exposure to anesthetics. However, the effects of GM1 ganglioside (GM1) on Αβ fibrillogenesis have not yet been reported. The current study was designed to examine whether the anesthetics propofol and thiopental are associated with Αβ assembly and GM1 expression on the neuronal cell surface. Methods: PC12N cells and cultured neuronal cells were treated with propofol or thiopental, and GM1 expression in treated and untreated cells was determined by the specific binding of horseradish peroxidase-conjugated cholera toxin subunit B (n = 5). The effects of an inhibitor of the γ-aminobutyric acid A receptor was also examined (n= 5). In addition, the effects of the anesthetics on GM1 liposome-induced Αβ assembly were investigated (n = 5). Finally, the neurotoxicity of the assembled Αβ fibrils was studied by the lactate dehydrogenase release assay (n = 6). Results: Propofol (31.2±4.7%) and thiopental (34.6±10.5%) decreased GM1 expression on the cell surface through the γ-aminobutyric acid A receptor. The anesthetics inhibited Αβ fibril formation from soluble Αβ in cultured neurons. Moreover, propofol and thiopental suppressed GM1-induced fibril formation in a cell-free system (propofol, 75.8±1.9%; thiopental, 83.6±1.9%) and reduced the neurotoxicity of a mixture containing Aβ and GM1 liposomes (propofol, 35.3±16.4%; thiopental, 21.3±11.6%). Conclusions: Propofol and thiopental have direct and indirect inhibitory effects on Αβ fibrillogenesis.

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The Tottori (D7N) and English (H6R) Familial Alzheimer Disease Mutations Accelerate Aβ Fibril Formation without Increasing Protofibril Formation

Journal of Biological Chemistry ◽

10.1074/jbc.m608220200 ◽

2006 ◽

Vol 282 (7) ◽

pp. 4916-4923 ◽

Cited By ~ 77

Author(s):

Yukiko Hori ◽

Tadafumi Hashimoto ◽

Yosuke Wakutani ◽

Katsuya Urakami ◽

Kenji Nakashima ◽

...

Keyword(s):

Alzheimer Disease ◽

Amyloid Fibril ◽

Amyloid Β ◽

Fibril Formation ◽

Amyloid Β Protein ◽

Protein Precursor ◽

Amyloid Fibril Formation ◽

Β Protein ◽

Familial Alzheimer Disease ◽

Aβ Production

A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid β-protein precursor or presenilins. Whereas some amyloid β-protein precursor mutations alter its metabolism through effects on Aβ production, the pathogenic effects of those that alter amino acid residues within the Aβ sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Aβ mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Aβ production, synthetic Aβ(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Aβ(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R Aβ were markedly inhibited despite enhanced fibril formation. These N-terminal Aβ mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Aβ peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.

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