Amyloid diseases: Abnormal protein aggregation in neurodegeneration

Alzheimer’s disease (AD) and Parkinson’s disease are the most common forms of age-related neurodegenerative disorders. The pathogenesis of these and other neurodegenerative diseases remains unclear, and effective treatments are currently lacking. However, recent studies from three diverse disciplines, neuropathology, genetics, and biophysics, have begun to converge on a novel target for therapeutic attack: ordered protein aggregation. Indeed, abnormal protein aggregation characterizes many, if not all, neurodegenerative disorders, not just AD and Parkinson’s disease, but also Creutzfeldt–Jakob disease, motor neuron diseases, the large group of polyglutamine disorders, including Huntington’s disease (1), as well as diseases of peripheral tissue like familial amyloid polyneuropathy (FAP). Many of these deposits were originally identified by their histochemical staining property, hence their designation as amyloid (starch-like). Subsequently, it was learned that amyloid deposits contain extremely insoluble protein fibrils that share similar morphological features (80- to 150-Å fibrils) but comprise many different proteins with no obvious sequence similarity. This review will focus on biophysical studies of protein aggregation in AD and FAP, where mechanistic models connecting pathological and genetic data to clinical disease are beginning to emerge. These two examples illustrate two ends of the biophysical spectrum: in one (AD), a flexible peptide is poised to form fibrils, whereas in the other (FAP), a stable globular tetramer must dissociate and partially unfold before forming a new stable fibril structure.