A critical analysis of postulated pathogenetic mechanisms in amyloidogenesis

This review has examined several of the major thrusts in amyloid research, past and present. The data concerning amyloid precursor quantity, primary protein and gene structure, and precursor proteolysis have shown that there are contradictions that must be resolved before these elements can be reamalgamated into a unified view of amyloidogenesis. One possibility is presented in Figure 2. A general hypothesis of amyloid formation that accounts for the uniformity of fibril structure, amyloid staining properties, and the specific selection of precursors and their specific anatomic localization in each form of amyloid has yet to be proposed. Some of these questions may be answered by an analysis of common structural constituents in amyloid deposits. Analyzing amyloid generation in the context of these common elements separates amyloid research into several specific areas (Figure 2). The first area concerns factors that govern the expression of amyloid precursor protein genes, thus providing adequate quantities of the precursor, if such a precursor pool does not already exist. Without such a pool, amyloid deposition clearly cannot occur. The second area concerns information as to where these precursors usually bind and/or exert their normal function. Once determined, this information will likely indicate the site or sites where the particular precursor may give rise to amyloid deposits. The last area concerns factors at these local sites that govern the interaction of the precursor with basement membrane or related extracellular matrix elements that would define both the site and the final common pathway for amyloid deposition.