Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the presence of cerebral amyloid plaque (reviewed by Selkoe, 1991), a highly ordered protein aggregate defined by its insolubility and fibrillar structure (Lansbury, 1992). The AD amyloid protein (p protein) is a secreted protein of unknown function that is overproduced in some but not all AD cases (Seubert et al., 1992; Shoji et al., 1992). Acausal relationship between amyloid formation and AD has not been proven, but the slow onset of symptoms appears to parallel the gradual deposition of amyloid. Therefore, it is important to understand the molecular mechanism of amyloid formation and to explain why the p protein aggregates in diseased individuals (Citron et al., 1992; Cai et al., 1993). In this review, a simple chemical explanation is proposed, based on the observation that in vitro amyloid formation bears a mechanistic resemblance to processes involving ordered protein aggregation (such as protein crystallization and microtubule formation), which will be referred to as nucleationdependent polymerizations. Like AD, the human prion diseases, Creutzfeldt-Jakob disease and Gertsmann-StrBussler-Scheinker disease, are characterized by the slow onset of neurodegeneration. Brain pathology in these diseases resembles that of AD (Prusiner, 1964; Baker and Ridley, 1992) and is also characterized by aggregation of a normal cellular protein, prion protein (PrP)(rather than the p protein), often in amyloid plaques (reviewed by Prusiner, 1991). In contrast with AD, the pathogenic nature of PrP aggregates has been established, thanks to extensive work on the transmissible prion disease, scrapie. The infective agent of scrapie may operate by accelerating the step in amyloid formation that is normally rate determining (Griffith, 1967; Prusiner, 1991). We propose that this step is mechanistically relevant to amyloid formation in human prion disease and in AD; it is the formation of an ordered nucleus, which is the defining characteristic of a nucleation-dependent polymerization. According to this hypothesis, the transmission of scrapie and the initiation of AD may both involve the seeding of amyloid formation.

Protein Solubility Is Normally Operationally Defined The measurement of protein solubility often reflects a kinetic effect rather than true thermodynamic solubility. For instance, when a protein solution appears to be clear throughout the course of an experiment, the protein is defined as soluble, although precipitation may eventually occur. The rate at which a protein polymerizes and precipitates is not necessarily related to its thermodynamic solubility. However, both properties may be relevant to the pathogenesis and treatment of amyloid diseases.