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

Abstract

Certain neurodegenerative disorders are characterized by the progressive accumulation of insoluble deposits of distinct misfolded proteins. In general, mutations causing inherited forms of the respective diseases affect the folding, aggregation and/or solubility of these proteins. In Alzheimer's disease (AD), amyloid β-protein (Aβ) production by regulated intramembrane proteolysis is crucial for pathogenicity. An unusual intramembrane cleavage generates various Aβ species, only one of which (the longest variant) is particularly prone to form potentially toxic oligomers. Soluble oligomeric assemblies of amyloidogenic proteins are increasingly thought to initiate disease-specific cytopathology and subsequent symptoms. Larger deposits, such as compacted Aβ plaques, seem to be relatively inert but might serve as reservoirs of diffusible oligomers. Oligomeric assemblies of amyloidogenic peptides from distinct neurodegenerative diseases — such as Parkinson's, AD, Huntington's and prion disorders — share common structural properties. Small oligomeric assemblies of Aβ have been specifically shown to impair long-term potentiation and dendritic spine structure in the hippocampus and to decrease memory in animals. Oligomeric species of Aβ are active targets for therapeutic intervention. Aβ immunotherapy, Aβ-aggregation inhibitors, allosteric modulators of γ-secretase and Aβ-degrading proteases can all reduce oligomeric Aβ, consequent neuronal degeneration and behavioural deficits in mouse models of AD. The first promising clinical data from AD human trials seem to support the potential of Aβ-directed immunotherapy that can neutralize oligomers. Similar therapeutic approaches based on oligomeric amyloidogenic species are likely to apply to other protein-folding diseases of the nervous system.