Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie?

Joseph T. Jerrett and Peter T. Lansbury, Jr. Department of Chemistry Massachusetts Institute of Technology Cambridge, Massachusetts 02139 Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the presence of cerebral amyloid plaque (reviewed by Selkoe, 1991), a highly ordered protein ag- gregate 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 forma- tion 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 mo- lecular mechanism of amyloid formation and to explain why the p protein aggregates in diseased individuals (Cit- ron et al., 1992; Cai et al., 1993). In this review, a simple chemical explanation is proposed, based on the observa- tion that in vitro amyloid formation bears a mechanistic resemblance to processes involving ordered protein ag- gregation (such as protein crystallization and microtubule formation), which will be referred to as nucleation- dependent 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 char- acterized 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 estab- lished, thanks to extensive work on the transmissible prion disease, scrapie. The infective agent of scrapie may oper- ate 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 ki- netic 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 precipi- tates is not necessarily related to its thermodynamic solu- bility. However, both properties may be relevant to the pathogenesis and treatment of amyloid diseases. Proteins can form different types of insoluble aggre- gates. Amorphous aggregates have multiple protein con- formations and ill-defined intermolecular interactions. In contrast, protein crystals are often characterized by a sin- gle protein conformation and a single well-defined intermo- lecular packing arrangement. Ordered noncrystalline polymers such as amyloid share these properties. In fact, amyloid can be thought of as a one-dimensional crystal in which packing in the plane perpendicular to the direction of fibril growth is nonuniform (Lansbury, 1992). Amor- phous aggregates can form rapidly when the protein con- centration exceeds the solubility. However, crystal formation requires time, owing to the kinetic barrier im- posed by nucleus formation, the rate-determining step. Ordered noncrystalline protein polymers such as amyloid share this requirement for nucleation. Nucleation-Dependent Polymerization Is Common Nucleation-dependent protein polymerization describes many well-characterized processes, including protein crystallization, microtubule assembly, flagellum assem- bly, sickle-cell hemoglobin fibril formation, bacteriophage procapsid assembly, and actin polymerization. A simple general mechanism is illustrated for the formation of a helical protein polymer in Figure 1. Nucleus formation re- quires a series of association steps that are thermodynam- ically unfavorable (K, > 1) because monomers contact the growing polymer at multiple sites, resulting in rapid polymerization/ growth. A distinctive feature of a nucleation-dependent polymer-