ReviewCommon mechanisms of amyloid oligomer pathogenesis in degenerative disease
Introduction
Therapeutic strategies that target disease mechanisms hold considerable promise for effectively treating or curing amyloid related degenerative diseases. The dilemma for medical scientists is to decide which of the pathological mechanisms to target for therapeutic development. Degenerative diseases share a striking number of common pathological features or events, such as evidence of membrane damage, oxidative stress, mitochondrial dysfunction up regulation of autophagy and cell death. Which mechanisms are primary and are they related in a causal sequence? In addition to the accumulation amyloid fibrils, these diseases also show evidence of oxidative damage, ion and metal dyshomeostasis, aberrant signal transduction, mitochondrial dysfunction and cell death. Recent evidence suggests that amyloid oligomers, which represent intermediates in the fibril formation process may be primarily responsible for amyloid pathogenesis, rather than the mature fibrils that accumulate as large aggregates [25], [36]. The purpose of this review is to explore the hypothesis that these common disease mechanisms may be causally related to common properties of amyloid oligomers that are shared among degenerative disease.
Section snippets
Common pathway of amyloid fibril formation
Amyloid fibrils accumulate in degenerative diseases as a consequence of the intermolecular hydrogen bonding of extended polypeptide strands that arise as a consequence of protein mis-folding. Amyloids from different diseases may share a common pathway for fibril formation. The initiating event is protein mis-folding or denaturation, which results in the acquisition of the ability to aggregate in an infinitely propagating fashion. Quasi-stable intermediate aggregates ranging from dimers up to
Common structure of amyloid oligomers and fibrils
Amyloids also have a number of structural features in common. Amyloid fibrils have a “cross-β” structure, which indicates that the backbone hydrogen bonding is parallel to the fibril axis [18], [34], [35]. Amyloids also bind characteristic dyes, like Congo red and thioflavin dyes, which may be a reflection of their common cross-β structure [38]. More recent structural characterization indicates that amyloid fibrils represent a generic, intermolecular hydrogen bonded structural motif that is not
Common primary mechanism of pathogenesis
Since different amyloid oligomers share a common structure and they are generically toxic to cells, this predicts that they have the same primary mechanism of toxicity in degenerative diseases. What is the primary mechanism of amyloid oligomer toxicity? If soluble oligomers have a common mechanism of toxicity, it predicts that they would act on the same primary target. This restricts number of potential targets to ones that are accessible to all of the different types of oligomers. Some
Common pathogenic pathways
The permeabilization of membranes by amyloid oligomers that has been reported as a common component of amyloid toxicity may represent the primary common mechanism of amyloid pathogenesis (Fig. 1). It may initiate a series of downstream pathological events that represents a common pathway of degeneration in amyloid-related diseases. These events that may lie immediately downstream from membrane permeabilization may constitute a core group of common pathological events that ultimately result in
Disease specific pathways
In addition to a common core of pathogenic pathways, unique, disease-specific events and pathways also characterize degenerative diseases. The simplest way of rationalizing their effects is to postulate that they lie upstream of the common pathways and have the common net effect of increasing the amount of mis-folded, aggregation competent proteins (Fig. 1). The most obvious class of disease specific events is mutations in the proteins that accumulate as amyloids in disease. These mutations are
Implications for therapeutic development
Understanding the relationships between pathological events pathways has significant implications for therapeutic development. Which pathways are primary and are they ordered in a causal sequence? Targeting downstream pathways may not be effective if there are multiple, parallel pathways or if the target is downstream from a significant source of pathogenesis. Targeting disease specific pathways, like Aβ-production, may be effective, but their effectiveness may be restricted to that specific
Acknowledgements
I sincerely thank the Larry L. Hillblom Foundation and the National Institutes of Health for support. The author is a consultant for Kinexis Inc.
References (58)
- et al.
Calcium signals induced by amyloid-β peptide and their consequences in neurons and astrocytes in culture
Biochim Biophys Acta
(2004) - et al.
Supramolecular structure in full-length Alzheimer's β-amyloid fibrils: evidence for a parallel β-sheet organization from solid-state nuclear magnetic resonance
Biophys J
(2002) - et al.
Prefibrillar amyloid protein aggregates share common features of cytotoxicity
J Biol Chem
(2004) - et al.
Assembly and aggregation properties of synthetic Alzheimer's A4/β-amyloid peptide analogs
J Biol Chem
(1992) - et al.
Structural organization of alpha-synuclein fibrils studied by site-directed spin labeling
J Biol Chem
(2003) - et al.
Soluble amyloid Aβ-(1–40) exists as a stable dimer at low concentrations
J Biol Chem
(1997) - et al.
Studies on the in vitro assembly of Aβ1–40: implications for the search for Aβ-fibril formation inhibitors
J Struct Biol
(2000) - et al.
Atomic force microscopy reveals defects within mica supported lipid bilayers induced by the amyloidogenic human amylin peptide
J Mol Biol
(2004) - et al.
Observation of metastable Aβ-amyloid protofibrils by atomic force microscopy
Chem Biol
(1997) - et al.
Aggregation and secondary structure of synthetic amyloid-β A4 peptides of Alzheimer's disease
J Mol Biol
(1991)