title: A model of amyloid's role in disease based on fibril fracture.
abstract: Although the correlative evidence relating the presence of amyloid fibrils and certain disease states (e.g. Alzheimer's disease and Type 2 Diabetes) is overwhelming, a direct causative role for amyloid has proved harder to establish. Current thinking links a narrow region of the aggregate protein size distribution, the so called 'early aggregate' domain to cellular toxicity. A troubling feature of this theory however is that the nucleated reaction mechanism by which amyloid formation is believed to occur results in a very low number concentration of early aggregates which are rapidly extended to form amyloid fibrils. This situation means that the concentration of early aggregates is very low at the time when they are supposedly at their most toxic. Here we adopt a novel explicit simulation strategy to examine a kinetic regime involving nucleated growth combined with fibril fragmentation under which this situation can be reversed so as to produce a high number concentration of small on-pathway toxic aggregates. Dependent upon the rate of fragmentation, the time scale for generation of toxic early aggregates may be coupled, uncoupled or disassociated from the time scale for the appearance of amyloid fibrils. Furthermore the model presents itself as a biochemical 'switch' transitioning between modes of amyloid induced cell death dependent upon either specific amyloid toxicity or non-specific solid mass induced tissue damage.
authors.affiliation: Institute of Basic Medical Science University of Tsukuba, Lab 225-B, Building D, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki-ken, 305-8577, Japan. damienhall@md.tsukuba.ac.jp
authors.forename: Damien
authors.initials: D
authors.lastname: Hall
authors.forename: Herman
authors.initials: H
authors.lastname: Edskes
mesh_terms: D000682:Amyloid / Q000502:physiology*; D016022:Case-Control Studies; D006801:Humans; D000683:Serum Amyloid P-Component / Q000502:physiology
chemical_list: D000682:Amyloid; D000683:Serum Amyloid P-Component