Protein Aggregation Associated with alzhiemer and Prion Diseases

Abstract

The brains of patients with Alzheimer's disease (AD), Creutzfeldt-Jakob disease (CJD), Kuru and others are characterized by an abundance of amyloid deposits. As long as the amyloid deposit could be described only by its histopathological morphology, these and other diseases appeared to have common molecular grounds, although the clinical pictures were different. Rudolf Virchow was the first who described the deposits in Alzheimer patients brains as “Eiweiss-Starke”(protein-starch) and therefore gave the name “amyloid”. Due to the work of Beyreuther and colleagues (see [11.1]) and Prusiner and colleagues (see [11.2]) it became known that the Alzheimer deposits consisted predominantly of the p-amyloid-peptide and those of CJD and Kuru of the prion protein, respectively, and that both proteins are encoded by a host nuclear gene. The molecular mechanism, cellular location and disease etiology, however, are quite different. Besides CJD and Kuru more human diseases like Gestmann-Straussler-Scheinker disease and familial fatal insomnia, but also animal diseases like scrapie in sheep and bovine spongiform encephalopathy (BSE) are closely connected with a pathological form of the prion protein, therefore denoted generally as “prion-diseases”. Most strikingly, and in contrast to AD, prion-diseases are transmissible, which led also to the name prion as proteinaceous infectious agent [11.3]. It is not yet known whether formation of insoluble deposits is a prerequisite of infectivity, but it is generally accepted that a pathological isoform of the prion protein, the so called Scrapie-isoform, PrPS c , is the major component of the brain deposits as well as of the infectious agent. During the infection event P r P S c is formed by a post-translational process from the cellular isoform P r P c. The relationship between the aggregate formation, the conformational transition of P r P c into PrPS c , and generation of infectivity and pathogenicity will be one of the major subjects of this chapter.