The use of conformation-specific
ligands has been closely linked to progress in the molecular characterization of
neurodegenerative diseases. Deposition of misfolded or misprocessed
proteins is now recognized as a hallmark of all
neurodegenerative diseases. Initially,
dyes like
Congo red and
thioflavin T were used as crudely conformation-specific
ligands for staining the beta-sheeted
protein components of
amyloid deposits in
neurodegenerative diseases such as
Alzheimer disease (AD) and
prion disease, the two diseases in which protein conformations were distinguished early on. This conformational characterization of extracellular
protein deposits with
dyes ultimately led to the identification of key players in the disease processes. The recent discovery of intermediate conformational species, i.e., soluble oligomers for AD and PK-sensitive PrP(Sc) for
prion disease, whose conformation and assembly are thought to be distinct from both the physiological and the fibrillar conformational states, replaced the former notion that the microscopic
protein deposits themselves caused disease. This insight and the generation of conformation-specific
monoclonal antibodies to these conformers further advanced diagnosis and the understanding of molecular mechanisms of AD and are likely to do so in other
neurodegenerative diseases. Here we review how conformer distinction performed by a variety of different techniques, including biophysical, biochemical, and antibody-based methods, led to the current molecular concepts of AD and the
prion diseases. We provide an outlook on the application of these techniques in advancing the understanding of molecular mechanisms of other
neurodegenerative diseases or degenerative brain conditions.