Raft -Lipide und Cholesterol-Ester als Bestandteile von humanen ex vivo Amyloid-Fibrillen (English shop)

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Amyloidoses are degenerative protein-storage diseases that primarily occur in old age. They represent a growing medical challenge with significant socioeconomic implications. Well-known examples include Alzheimer’s disease and prion diseases. To date, more than 20 amyloid proteins have been identified. In the course of the disease, these proteins aggregate and deposit within tissues as fibrils—a hallmark of amyloidoses—characterized by a high content of β-sheet structures. The structure of these amyloid fibrils remains consistent, regardless of the specific fibril proteins involved, the clinical symptoms, the affected tissues, or whether the formation is induced or spontaneous. The deposition process can occur intracellularly or extracellularly and may be localized to specific organs or manifest systemically, ultimately leading to tissue damage and death.
The pathogenic mechanism underlying amyloidoses remains largely poorly understood. This thesis explores the role of lipids in the pathogenesis of these conditions.
The objective of this doctoral research was to analyze the proteins and lipids present in human ex vivo amyloid fibrils to gain insight into their pathogenic mechanisms. The amyloid samples were extracted from tissues affected by amyloidosis by Prof. Dr. Reinhold P. Linke, Prof. Dr. Mordechai Pras, and Prof. Dr. Peter Davies. Given the limited quantity of patient-derived material, it was necessary to establish sensitive, quantitative micro-analytical methods capable of precisely determining the protein and lipid components within the amyloid fibrils.
The collected material was characterized as amyloid, and the identity of the fibril proteins was confirmed using protein-analytical techniques. Quantification of the proteins
revealed that additional components were co-purified alongside them.
An analysis of the lipid content of the amyloid fibrils identified a selective
lipid pattern in all samples, which differed from the lipid composition found in control tissue.
A notably low proportion of phospholipids was observed. Lipids known to form
lipid microdomains (“lipid rafts”)—specifically cholesterol and sphingomyelin—were found to be highly enriched.
Furthermore, high levels of cholesterol esters were detected in the human ex vivo amyloid fibrils.
The selective association of these lipids with the amyloid fibrils—independent of the
specific fibril protein—suggests that the pathological processes underlying amyloidoses
generally occur within “lipid rafts.” In this context, the cholesterol esters—which are
primarily localized within the core of lipoproteins—appear to play a specific role in the
aggregation of the serum proteins under investigation.