Elsevier

Neurobiology of Aging

Volume 27, Issue 4, April 2006, Pages 570-575
Neurobiology of Aging

Review
Common mechanisms of amyloid oligomer pathogenesis in degenerative disease

https://doi.org/10.1016/j.neurobiolaging.2005.04.017Get rights and content

Abstract

Many age-related degenerative diseases, including Alzheimer's, Parkinson's, Huntington's diseases and type II diabetes, are associated with the accumulation of amyloid fibrils. The protein components of these amyloids vary widely and the mechanisms of pathogenesis remain an important subject of competing hypotheses and debate. Many different mechanisms have been postulated as significant causal events in pathogenesis, so understanding which events are primary and their causal relationships is critical for the development of more effective therapeutic agents that target the underlying disease mechanisms. Recent evidence indicates that amyloids share common structural properties that are largely determined by their generic polymer properties and that soluble amyloid oligomers may represent the primary pathogenic structure, rather than the mature amyloid fibrils. Since protein function is determined by the three-dimensional structure, the fact that amyloids share generic structures implies that they may also share a common pathological function. Amyloid oligomers from several different proteins share the ability to permeabilize cellular membranes and lipid bilayers, indicating that this may represent the primary toxic mechanism of amyloid pathogenesis. This suggests that membrane permeabilization may initiate a core sequence of common pathological events leading to cell dysfunction and death that is shared among degenerative diseases, whereas pathological events that are unique to one particular type of amyloid or disease may lie in up stream pathways leading to protein mis-folding. Although, these upstream events may be unique to a particular disease related protein, their effects can be rationalized as having a primary effect of increasing the amount of mis-folded, potentially amyloidogenic proteins.

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.

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