ABSTRACT

The proteopathies comprise numerous diseases of the brain and other organs that are characterized by the aggregation, accumulation, and toxicity of specific proteins (Koo et al., 1999; Walker and LeVine, 2000a, 2000b; Bucciantini et al., 2002). The diversity of proteins that can form pathogenic assemblies is substantial (Chiti and Dobson, 2006); in many instances, the proteins form amyloid, which refers to masses of fibrillar protein that are birefringent under crossed polarizing filters after staining with the dye Congo red. Recently, several amyloid-like protein assemblies have been discovered that serve normal biological functions in a range of species (Chiti and Dobson, 2006; Badtke et al., 2009; Luheshi and Dobson, 2009; Maury, 2009; Wickner et al., 2010; Heinrich and Lindquist, 2011). While it is increasingly clear that aberrant proteinaceous assemblies play a key role in the development of the mammalian proteopathies, little is known about the molecular structure of aggregated proteins in vivo, or

7.1 Protein Aggregation and Neurodegenerative Disease .................................. 231 7.2 Prion Disease ................................................................................................ 232 7.3 Protein Strains ..............................................................................................234 7.4 Molecular Probes for Conformational Variants of Amyloidogenic

Proteins ..................................................................................................... 235 7.5 Pittsburgh Compound B (PIB) as a Molecular Probe for Aβ ..................... 236 7.6 PIB Binding in Nonhuman Primates ............................................................ 236 7.7 Anomalous PIB Binding in Alzheimer’s Disease ........................................ 238 7.8 Conclusions ................................................................................................... 239 Acknowledgments .................................................................................................. 239 References .............................................................................................................. 239

about how their misfolding is initiated and propagated in diseased tissue. The development of diagnostic and therapeutic agents will be accelerated by a better understanding of how proteins become corrupted and proliferate their abnormal features in vivo; the mechanistic commonalities among the diseases of protein aggregation suggest the possibility of a unified approach to treatment (Walker and LeVine, 2002).