Methods for Studying and Structure–Function Relationships of Non-Fibrillar Protein Assemblies in Alzheimer's Disease and Related Disorders
Pp. 291-374 (84)
Farid Rahimi and Gal Bitan
Several neurodegenerative diseases, including Alzheimer's, Parkinson's,
Huntington's, and prion diseases, are characterized by intra- and/or extracellular
deposition of fibrillar proteinaceous aggregates, and by extensive, neuron loss. Related
non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses,
and other organ-specific diseases, such as dialysis-related amyloidosis and type-2
diabetes, also are characterized by deposition of aggregated proteins. It is debated
whether these hallmark lesions are causative. Substantial evidence suggests that the
aggregates are the end state of protein misfolding whereas the actual culprits likely are
transient, non-fibrillar assemblies preceding the aggregates. The non-fibrillar,
oligomeric assemblies are believed to initiate pathogenesis, leading to synaptic
dysfunction, neuron loss, and pathognomonic brain atrophy. It is hypothesized that nonfibrillar
assemblies or fibril-derived fragments may promote anatomical progression of
pathology, or even disease transmissibility, akin to misfolded prions.
Amyloid β-protein (Aβ), which is believed to cause Alzheimer's disease, is considered
an archetypal amyloidogenic protein. Intense studies have led to nominal, functional,
and structural descriptions of oligomeric Aβ assemblies. However, the dynamic and
metastable nature of Aβ oligomers renders their study difficult. Different results
generated using different methodologies under different experimental settings further
complicate this complex area of research and identification of the exact pathogenic
assemblies in vivo seems daunting.
In this chapter we review structural, functional, and biological experiments used to
produce and study non-fibrillar Aβ assemblies, and highlight similar studies of proteins
involved in related diseases. We discuss challenges that contemporary researchers are
facing and future research prospects in this demanding, yet highly important, field.
David Geffen School of Medicine, University of California at Los Angeles, Neuroscience Research Building 1, Room 451, 635 Charles E. Young Drive South, Los Angeles, CA 90095-7334, USA.