Molecular mechanisms underlying initiation of amyloid fibril formation

Abstract

Deposition of aggregated amyloid β-protein (Aβ), a proteolytic cleavage product of the amyloid precursor protein (APP), is a fundamental pathological event in the development of Alzheimer’s disease (AD) [1]. Although a great deal of effort has been made to clarify the pathogenesis of AD, we are still far from a complete understanding of the molecular mechanism underlying the initiation of amyloid fibril formation. In regard to the mechanism of protein aggregation, the nucleation-dependent polymerization theory is widely accepted [2]. In this model, a long lag-time is required for nucleation. Furthermore, the concentration of a given protein is required to be greater than a critical level for nucleation. In regard to the polymerization of Aβ in vitro,Aβ at concentrations below 20 μM is unlikely to aggregate spontaneously. Considering that the physiological concentration of Aβ in biological fluids, including the cerebrospinal fluid, sera and culture media, is as low as 10 nM, even in the case of the expression of some genes responsible for familial AD which could induce increased generation of Aβ [3–6], one would assume that Aβ probably aggregates in brains in the presence of pathological chaperones such as apolipoprotein E4, α1-antichymotrypsin and proteoglycans. Alternatively, a pathological Aβ species with the ability to act as a seed or a template for fibril formation could be generated via a conformational alteration of Aβ, as has been postulated for the development of prion diseases [7]. In this chapter, I describe two novel Aβspecies with seeding ability, which were identified in the brains with AD or in culture media in our studies [8–10].