The amyloidoses constitute a large group of diseases in which misfolding of extracellular protein has a prominent role. This dynamic process, which occurs in parallel with or as an alternative to physiologic folding, generates insoluble, toxic protein aggregates that are deposited in tissues in bundles of b-sheet fibrillar protein. At least 21 different proteins have been recognized as causative agents of amyloid diseases. Despite having heterogeneous structures and functions, all these proteins can generate morphologically indistinguishable amyloid fibrils.
The conversion of the structure of the native protein into a predominantly antiparallel b-sheet secondary structure (in which the N- and C-terminals are oriented in opposite directions) is a pathologic process closely related to physiologic protein folding. In amyloid disease, potentially pathogenic misfolded proteins can form in different ways. The protein may have an intrinsic propensity to assume a pathologic conformation, which becomes evident with aging (e.g., normal transthyretin in patients with senile systemic amyloidosis). Another mechanism is the replacement of a single amino acid in the protein, as occurs in hereditary amyloidosis. A third mechanism is proteolytic remodeling of the protein precursor, as in the case of b-amyloid precursor protein (APP) in Alzheimer’s disease. These mechanisms can act independently or in association with one another. In addition to the intrinsic amyloidogenic potential of the pathogenic protein, other factors may act synergistically in amyloid deposition.
The deposition of large amounts of fibrillar material can subvert the tissue architecture and consequently cause organ dysfunction. Amyloid fibrils may also cause organ dysfunction by interacting with local receptors, such as RAGE. In Alzheimer’s disease, an inflammatory response in the cerebral cortex elicited by the progressive accumulation of Ab contributes to the pathogenesis of the disease. Soluble fibril precursors are likely to be the quaternary structures that mediate cellular toxicity through a mechanism that causes oxidative stress and activates the apoptotic pathway. Mature amyloid fibrillary deposits are inactive proteinaceous reservoirs that are in equilibrium with smaller, putatively toxic assemblies (ordered aggregates).