The amyloid state and its association with protein misfolding diseases

Abstract

The phenomenon of protein aggregation and amyloid formation has become the subject of rapidly increasing research activities across a wide range of scientific disciplines. Such activities have been stimulated by the association of amyloid deposition with a range of debilitating medical disorders, from Alzheimer's disease to type II diabetes, many of which are major threats to human health and welfare in the modern world. It has become clear, however, that the ability to form the amyloid state is more general than previously imagined, and that its study can provide unique insights into the nature of the functional forms of peptides and proteins, as well as understanding the means by which protein homeostasis can be maintained and protein metastasis avoided.

Ultrasensitive Measurement of Ca2+ Influx into Lipid Vesicles Induced by Protein Aggregates

“…The conversion of soluble proteins into fibrillar amyloid deposits is a hallmark of a range of increasingly prevalent neurodegenerative disorders including Alzheimer's Disease (AD) and Parkinson Disease (PD) 1, 2, 3, 4. It has been reported that the species formed during the aggregation reactions have a toxic effect on cells 5, 6, 7, 8.…”

“…It has been reported that the species formed during the aggregation reactions have a toxic effect on cells 5, 6, 7, 8. Several possible mechanisms of cellular damage have been identified with relative contributions that depend on both the concentrations and the types of aggregates present 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. The aggregation process that results in the formation of oligomers may contribute to cellular damage 12, 13, 14, 15.…”

“…The aggregation process that results in the formation of oligomers may contribute to cellular damage 12, 13, 14, 15. Some of these mechanisms are thought to involve specific binding to receptors on the cell membrane1, 5, 9 while others appear to be the consequence of non‐specific membrane disruption 1, 3, 5, 9, 16. A body of data suggests that small soluble aggregates, often called oligomers, rather than mature fibrils, are able to cause the membrane to become permeable to Ca 2+ resulting in Ca 2+ influx and the disruption of Ca 2+ homeostasis 2, 3, 5, 9, 17, 18.…”

“…Some of these mechanisms are thought to involve specific binding to receptors on the cell membrane1, 5, 9 while others appear to be the consequence of non‐specific membrane disruption 1, 3, 5, 9, 16. A body of data suggests that small soluble aggregates, often called oligomers, rather than mature fibrils, are able to cause the membrane to become permeable to Ca 2+ resulting in Ca 2+ influx and the disruption of Ca 2+ homeostasis 2, 3, 5, 9, 17, 18. Therefore, it is important to quantify and characterize these species within aggregation mixtures in vitro as well as to be able to perform measurements in biological samples, such as cerebrospinal fluid (CSF) 19.…”

“…Therefore, it is important to quantify and characterize these species within aggregation mixtures in vitro as well as to be able to perform measurements in biological samples, such as cerebrospinal fluid (CSF) 19. However, these oligomers are known to be present at low abundance and to be highly heterogeneous in nature, in terms of both their size and structure 1, 2, 3, 4, 9, 10, 16…”