All tags Neuroscience Beta amyloid in Alzheimer's disease: conformational variation

Beta amyloid in Alzheimer's disease: conformational variation

Structural variation of beta amyloid (Aβ) may explain the complex pathology of Alzheimer’s disease and highlights the need for conformation-specific antibodies.

Conformational variation and Alzheimer’s disease

Alzheimer’s disease is a complex neurodegenerative condition with symptoms varying between patients. The case for Aβ playing a central role in disease pathology is compelling, yet its precise role remains unclear.

A characteristic feature of Alzheimer’s disease is the presence of plaques within the brain. These plaques are formed by monomeric Aβ spontaneously assembling into soluble oligomers, which cluster together to form insoluble fibrils. Evidence suggests a role for both soluble oligomers and insoluble fibrils in Alzheimer’s disease pathology, but their exact contributions are still under debate.

One barrier to understanding the role of Aβ in Alzheimer’s disease is the lack of correlation between Aβ in the brain and the cognitive ability of patients. For example, some patients with beta Aβ deposits show no symptoms of Alzheimer’s disease at all1–3.

The answer to Alzheimer’s disease heterogeneity may lie in structural variations of Aβ, which can form polymorphic Aβ oligomers in a process known as segmental polymorphism. This is where the segments that form beta sheets vary between different fibril structures4–6.

It is therefore likely that, similar to prion diseases, unique forms of structurally distinct Aβ are deposited in different places and at different times in the brains of Alzheimer’s disease patients. However, as yet it remains unclear which types of deposit are more closely linked with the cognitive symptoms of the disease7.

The need for conformation-specific antibodies

With increasing evidence to support the biomedical importance of Aβ structural variation, it is clear that conformation-specific Aβ imaging reagents will play a central role in the future of Alzheimer’s research.

A recent study in humans highlighted the clinical relevance of Aβ structural variation. Tissue taken from two Alzheimer’s disease patients with distinct clinical histories revealed that each patient had a predominant Aβ fibril structure; however, the dominant structure was different in each patient8.

Studies in mice and cultured cells have also supported the biological relevance of Aβ structural variation. Structurally distinct Aβ fibrils cause varying levels of toxicity in neuronal cultures, while mice given Aβ from different sources develop distinct patterns of Aβ deposition within the brain9,10.

Furthermore, the complexity of Aβ structure is convincingly reflected by the immune system, with research showing that the antibodies produced in response to Aβ fibrils are diverse, reflecting their structural variation11,12.

Considering all evidence, it is becoming increasingly clear that a single antibody will not be sufficient to study or target all the possible pathological aggregates of Aβ contributing to Alzheimer’s disease. This makes conformation-specific Aβ antibodies an essential tool for the future of Alzheimer’s disease research13–16.

Explore conformation-specific Aβ antibodies



References

1. Castellani R J, Lee H G, Zhu X, Perry G, & Smith M A (2008). Alzheimer’s disease pathology as a host response. J of Neuropath Exp Neur, 67, 523.

2. Dickson D W, Crystal H A, Mattiace L A, Masur D M, Blau A D, Davies P et al. (1992). Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol of aging, 13, 179-189.

3. Knopman D S, Parisi J E, Salviati A, Floriach-Robert M, Boeve B F, Ivnik R J et al. (2003). Neuropathology of cognitively normal elderly. J of Neuropath Exp Neur, 62, 1087-1095.

4. Schütz A K, Vagt T, Huber M, Ovchinnikova O Y, Cadalbert R, Wall J et al. (2015). Atomic‐Resolution Three‐Dimensional Structure of Amyloid β Fibrils Bearing the Osaka Mutation. Angewandte Chemie International Edition, 54, 331-335.

5. Tycko R (2015). Amyloid Polymorphism: Structural Basis and Neurobiological Relevance. Neuron, 86, 632-645.

6. Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M et al. (2015). A [beta](1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nature structural & molecular biology 22, 499-505.

7. Hatami A, Albay III R, Monjazeb S, Milton S, Glabe C (2014). Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. J Biol Chem 289, 1–13.

8. Lu J X, Qiang W, Yau W M, Schwieters C D, Meredith S C, & Tycko R (2013). Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell, 154, 1257-1268.

9. Petkova, A T, Leapman R D, Guo Z, Yau W M, Mattson M P, & Tycko R (2005). Self-propagating, molecular-level polymorphism in Alzheimer's ß-amyloid fibrils. Science, 307, 262-265.

10. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E et al. (2006). Exogenous induction of cerebral ß-amyloidogenesis is governed by agent and host. Science, 313, 1781-1784.

1. Castellani R J, Lee H G, Zhu X, Perry G, & Smith M A (2008). Alzheimer’s disease pathology as a host response. J of Neuropath Exp Neur, 67, 523.

2. Dickson D W, Crystal H A, Mattiace L A, Masur D M, Blau A D, Davies P et al. (1992). Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol of aging, 13, 179-189.

3. Knopman D S, Parisi J E, Salviati A, Floriach-Robert M, Boeve B F, Ivnik R J et al. (2003). Neuropathology of cognitively normal elderly. J of Neuropath Exp Neur, 62, 1087-1095.

4. Schütz A K, Vagt T, Huber M, Ovchinnikova O Y, Cadalbert R, Wall J et al. (2015). Atomic‐Resolution Three‐Dimensional Structure of Amyloid β Fibrils Bearing the Osaka Mutation. Angewandte Chemie International Edition, 54, 331-335.

5. Tycko R (2015). Amyloid Polymorphism: Structural Basis and Neurobiological Relevance. Neuron, 86, 632-645.

6. Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M et al. (2015). A [beta](1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nature structural & molecular biology 22, 499-505.

7. Hatami A, Albay III R, Monjazeb S, Milton S, Glabe C (2014). Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. J Biol Chem 289, 1–13.

8. Lu J X, Qiang W, Yau W M, Schwieters C D, Meredith S C, & Tycko R (2013). Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell, 154, 1257-1268.

9. Petkova, A T, Leapman R D, Guo Z, Yau W M, Mattson M P, & Tycko R (2005). Self-propagating, molecular-level polymorphism in Alzheimer's ß-amyloid fibrils. Science, 307, 262-265.

10. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E et al. (2006). Exogenous induction of cerebral ß-amyloidogenesis is governed by agent and host. Science, 313, 1781-1784.

11. Hatami A, Albay III R, Monjazeb S, Milton S, Glabe C (2014). Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. J Biol Chem 289, 1–13.

12. Pensalfini A, Albay R, Rasool S, Wu J W, Hatami A, Arai H et al. (2014). Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiology of disease, 71, 53-61.

13. Kayed R, Head E, Thompson J L, McIntire T M, Milton S C, Cotman C W, & Glabe C G (2003). Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science, 300, 486-489.

14. Kayed R, Head E, Sarsoza F, Saing T, Cotman, C W, Necula M et al. (2007). Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegen, 2, 18.

15. Kayed R, Pensalfini A, Margol L, Sokolov Y, Sarsoza F, Head E et al. (2009). Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer. J Biol Chem, 284, 4230-4237.

16. Kayed R, Canto I, Breydo L, Rasool S, Lukacsovich T, Wu J et al. (2010). Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Abeta oligomers. Mol Neurodegen, 5, 57.

Sign up