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Apolipoprotein E inhibits the depolymerization of beta 2-microglobulin-related amyloid fibrils at a neutral pH
I Yamaguchi1, K Hasegawa, N Takahashi
1Department of Pathology, Fukui Medical University, Fukui 910-1193, Japan.
Abstract:
beta 2-Microglobulin-related (A beta 2M) amyloidosis is a common and serious complication in patients on long-term hemodialysis, and beta 2-microglobulin (beta 2-m) is a major structural component of A beta 2M amyloid fibrils. Fluorescence spectroscopic analysis with thioflavin T and electron microscopic study revealed that A beta 2M amyloid fibrils readily depolymerize into monomeric beta 2-m at a neutral to basic pH. Circular dichroism analysis revealed that soon after the initiation of the depolymerization reaction at pH 7.5, the characteristic spectrum of beta 2-m in A beta 2M amyloid fibrils changes to resemble that of monomeric beta 2-m at pH 7.5. Apolipoprotein E (apoE), a representative amyloid-associated protein, formed a stable complex with A beta 2M amyloid fibrils and inhibited the depolymerization of A beta 2M amyloid fibrils dose-dependently in a range of 0--10 microM. These results showed that apoE could enhance the deposition of amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of beta 2-m in the fibrils.
Insights
Beta 2-microglobulin (beta 2-m) amyloid fibrils depolymerize at neutral to basic pH. Apolipoprotein E stabilizes these fibrils, potentially enhancing amyloid deposition in vivo.
Area of Science:
- Biochemistry
- Molecular Biology
- Medical Science
Background:
- Beta 2-microglobulin (beta 2-m) amyloidosis is a serious complication for hemodialysis patients.
- Beta 2-microglobulin (beta 2-m) is a key structural component of amyloid fibrils.
Purpose of the Study:
- To investigate the depolymerization of beta 2-microglobulin amyloid fibrils.
- To determine the effect of apolipoprotein E (apoE) on beta 2-m amyloid fibril stability.
Main Methods:
- Fluorescence spectroscopy (Thioflavin T) and electron microscopy were used to study A beta 2M amyloid fibrils.
- Circular dichroism analyzed conformational changes during depolymerization.
- Apolipoprotein E's interaction with A beta 2M amyloid fibrils was assessed.
Main Results:
- A beta 2M amyloid fibrils depolymerize into monomeric beta 2-m at neutral to basic pH.
- Apolipoprotein E formed a stable complex with A beta 2M amyloid fibrils.
- Apolipoprotein E inhibited fibril depolymerization in a dose-dependent manner.
Conclusions:
- A beta 2-microglobulin amyloid fibrils are unstable at neutral to basic pH.
- Apolipoprotein E stabilizes beta 2-m amyloid fibrils by binding to them.
- Apolipoprotein E may enhance in vivo amyloid deposition by stabilizing beta 2-m fibrils.