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

Key Points

  • 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.

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 β-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.

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Figure 1: Amyloid β-protein generation by normal proteolytic processing of β-amyloid precursor protein.
Figure 2: Naturally secreted SDS-stable a myloid β-protein oligomers block hippocampal long-term potentiation in vivo.
Figure 3: Therapeutic approaches targeting amyloid β-protein production and oligomerization.

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Acknowledgements

We thank D. Teplow, G. Multhaup, E. Mandelkow and D. Walsh as well as the members of our laboratories for helpful discussions. We also thank M. Neumann for providing the figures that are included in Box 1.

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Christian Haass is a consultant for Boehringer Ingelheim Pharma KG. Dennis J. Selkoe is a consultant for Elan, plc.

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Glossary

Amyloid

Tissue deposits of insoluble, proteinaceous fibrils that are rich in β-pleated sheet structure and therefore bind to the histochemical dye Congo red in a polarized manner.

Lewy body

(LB). A deposit of α-synuclein typically found in neuronal cell bodies of patients with Parkinson's disease or related disorders.

Lewy neurite

(LN). A deposit of α-synuclein typically found in swollen neuronal processes of patients with Parkinson's disease or related disorders.

Amyloid plaques

Spherical extracellular deposits predominantly composed of the amyloid β-peptide and found in the brains of all cases of Alzheimer's disease.

Neurofibrillary tangle

An intraneuronal filamentous aggregate composed of abnormally phosphorylated tau protein found in several human neurodegenerative disorders, including Alzheimer's disease.

Regulated intramembrane proteolysis

(RIP). Regulated cleavage of the luminal domain of certain membrane proteins is followed by a constitutive cleavage in the transmembrane domain. At least in some cases this process is involved in signalling pathways.

Intracellular domain

(ICD). One of the cleavage products of intramembrane proteolysis in the RIP pathway, it is liberated into the cytosol and in some cases targeted to the nucleus.

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Haass, C., Selkoe, D. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat Rev Mol Cell Biol 8, 101–112 (2007). https://doi.org/10.1038/nrm2101

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