Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide

Abstract

The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

“…The imbalance in overall protein homeostasis is a crucial factor in the development of heritable age‐related neurodegenerative diseases and during normal aging (Dobson, 2003; Vacher et al ., 2005; Zhang et al ., 2005; Arslan et al ., 2006; Haass & Selkoe, 2007; Morimoto, 2008). Achieving and maintaining the correct three‐dimensional protein structure is a continuous struggle within cells.…”

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.…”

“…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…”