[Frontiers in Bioscience 15, 373-396, January 1, 2010]

Methods and models in neurodegenerative and systemic protein aggregation diseases

Ann-Christin Brorsson1, Janet R. Kumita2, Ian MacLeod3,4, Benedetta Bolognesi2, Elena Speretta4, Leila M. Luheshi2,4, Tuomas P. J. Knowles5 David A. Lomas3, Christopher M. Dobson2, Damian C. Crowther3,4

1Molecular Biotechnology/IFM, Linkoping University, SE-581 83, Linkoping, Sweden, 2Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK, 3Cambridge Institute for Medical Research, Wellcome/MRC Building, Hills Road, Cambridge, CB2 0XY, UK, 4Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK, Nanoscience Centre, University of Cambridge, J. J. Thomson Avenue, Cambridge, CB3 0FF, UK

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The beta-amyloid peptide and Alzheimer's disease
3.1. Preparation and handling of the Abeta peptide
3.2. In vitro aggregation of the Abeta peptide
3.3. Abeta pathogenicity
4. Lysozyme and Systemic Amyloidosis
4.1. In vitro characterization of lysozyme fibril formation
4.2. Understanding lysozyme aggregation in vivo
5. Serpins and familial encephalopathy with neuroserpin inclusion bodies
5.1. Serpins and the serpinopathies
5.2. Neuroserpin and FENIB
5.3. Characterization of neuroserpin polymerization in vitro and in cell culture
5.4. Animal models of FENIB
6. Perspective
7. Acknowledgments
8. References

1. ABSTRACT

Protein misfolding and aggregation are implicated in a wide range of increasingly prevalent human diseases ranging from dementia to diabetes. In this review we discuss the current experimental strategies that are being employed in the investigation of the pathogenesis of three important protein misfolding disorders. The first, Alzheimer's disease (AD), is the most prevalent neurodegenerative disease and is thought to be initiated by the aggregation of a natively unstructured peptide called amyloid beta (Abeta). We discuss methods for the characterization of the aggregation properties of Abeta in vitro and how the results of such experiments can be correlated with data from animal models of disease. We then consider another form of amyloidosis, where a systemic distribution of amyloid deposit is caused by aggregation and deposition of mutational variants of lysozyme. We describe how experiments in vitro, and more recently in vivo, have provided insights into the origins of this disease. Finally we outline the varied paradigms that have been employed in the study of the serpinopathies, and in particular, a dementia caused by neuroserpin polymerization.