Biological Membranes as Protein Aggregation Matrices and Targets of Amyloid Toxicity - Protein Misfolding and Cellular Stress in Disease and Aging - page 222

Chapter 15
Biological Membranes as Protein Aggregation Matrices
and Targets of Amyloid Toxicity
Monica Bucciantini and Cristina Cecchi
Abstract
Aberrantly folded proteins and peptides are hallmarks of amyloid diseases. A deeper knowledge of the
pathways leading to the formation of amyloid protein aggregates and of the mechanisms of their cytotox-
icity is fundamental for a better understanding of several human diseases with amyloid deposition.
Increasing evidence indicates that amyloids arising from different peptides and proteins behave similarly
as for their cytotoxic effects. In general, different cell susceptibility to toxic protein aggregates depends
on the efficiency of different cell types to accumulate amyloid precursors at their plasma membrane with
subsequent growth of pre-fibrillar and fibrillar entities, resulting in membrane perturbation and cell dam-
age. Actually, protein-lipid interaction displays a twofold aspect: on the one hand, the presence of a lipid
membrane may influence protein unfolding and the aggregation process; on the other hand, protein
aggregates may modify membrane structure and permeability. Understanding the molecular basis of the
membrane-protein interaction (but, more extensively, of the surface-protein interaction) may help elu-
cidating some of the factors affecting protein misfolding and aggregation in vivo . This topic has been
investigated by a variety of techniques such as atomic force microscopy, transmission electron micros-
copy, confocal laser microscopy and flow cytometric analysis. In this overview, such techniques will be
reviewed with special emphasis to their use in protein aggregation studies.
Key words: Plasma membranes, Amyloid aggregates, Loss of membrane integrity, Atomic force
microscopy, Electron microscopy, Confocal laser microscopy, Flow cytometry
1. Introduction
An increasing body of evidence raised in the last few years has
focussed the attention of the researchers on the high cytotoxic
potential of small, prefibrillar protein aggregates arising initially
in the path of protein fibrillization, even when they are formed
in vitro from peptides or proteins not associated with any protein
deposition disease ( 1 ). These data have led to propose that such
prefibrillar assemblies share basic structural features that, at least