Conformation-Specific Aβ Antibodies – An Essential Tool for the Future of Alzheimer’s Disease Research

Introduction

The complex pathology of Alzheimer’s disease may be known from the structural variation of beta amyloid (Aβ), which also emphasizes the need for conformation-specific antibodies.

Conformational Variation and Alzheimer’s Disease

Alzheimer’s disease is a complicated neurodegenerative condition showing symptoms that differ from patient to patient. The case for Aβ playing a vital role in disease pathology is compelling, yet its precise role remains unclear.

Alzheimer’s disease is characterized by the existence of plaques in the brain. The formation of insoluble fibrils due to clustering together of soluble oligomers formed by the spontaneous assembly of monomeric Aβ is the cause of formation of these plaques.

According to study results, both insoluble fibrils and soluble oligomers play a role in Alzheimer’s disease pathology, yet their precise role remains unclear.

There is no correlation between Aβ within the brain and the cognitive ability of patients, which is a major obstacle to understanding the role Aβ potentially plays in Alzheimer’s disease. For instance, some patients who have beta Aβ deposits do not show any symptoms of Alzheimer’s disease1–3.

The structural variations of Aβ may provide the answer to Alzheimer’s disease heterogeneity. Polymorphic Aβ oligomers can be formed by Aβ in a process called segmental polymorphism, where the segments forming beta sheets have different fibril structures4–6.

Hence, like prion diseases, the deposition of unique forms of structurally distinct Aβ occurs in different places and at different times within the brains of patients with Alzheimer’s disease, but which types of deposit are responsible for the cognitive symptoms of the disease is still under debate7.

The Need for Conformation-specific Antibodies

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

The clinical relevance of Aβ structural variation was highlighted in a recent study conducted in humans. Tissues collected from two Alzheimer’s disease patients having distinct clinical histories showed the presence of a predominant Aβ fibril structure in each patient; however, the dominant structure was different in each patient8.

Studies conducted in cultured cells and mice have also provided evidence in support of 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.

Moreover, the immune system convincingly reflects the complexity of Aβ structure, with study results showing that the antibodies generated in response to Aβ fibrils are diverse, showing their structural variation11,12.

Taking into account all evidence, it is very clear that it is not sufficient to use a single antibody to study or target all the potential pathological aggregates of Aβ that contribute to Alzheimer’s disease. This confirms that conformation-specific Aβ antibodies will serve as a vital tool for the future of Alzheimer’s disease research13–16.

Conformation-specific Amyloid Beta Antibodies

Abcam plc offers a wide range of antibodies to distinguish between the conformational variation in amyloid structures.

Amyloid beta (Aß) plaques show diverse conformations in Alzheimer's disease, causing structural variants with distinct pathologies. Abcam, in partnership with Professor Charles Glabe (UC Irvine), created rabbit monoclonal antibodies against Aß 1–42 fibrils that are capable of distinguishing between the conformational variation in amyloid structures.

  • Human Aß (1–42) fibril immunogen
  • Rabbit monoclonal antibodies for high affinity and specificity
  • Validated using dot blot and IHC-P
  • Published in The Journal of Biological Chemistry

Antibody Reactivity in Human and Mouse Alzheimer's Disease Brain

Antibody name

Antibody ID

Human Alzheimer's brain specificity shown by IHC**

Alzheimer's mouse model* brain specificity shown by IHC**

Anti-amyloid fibril antibody [mOC22] - conformation-specific

ab205339

Frontal cortex plaques

Layer V cortical and CA1 pyramidal neurons

Anti-beta amyloid 1-42 antibody [mOC23] - conformation specific

ab205340

Subset of frontal cortex plaques

Hippocampal plaques

Anti-beta amyloid 1-42 antibody [mOC31] - conformation-specific

ab201059

Vascular amyloid deposits

N/A

Anti-beta amyloid 1-4 antibody [mOC64] - conformation-specific

ab201060

Frontal cortex plaques

N/A

Anti-amyloid fibril antibody [mOC78] - conformation specific

ab205341

Intracellular/nuclear, frontal cortex plaques

Layer V cortical neurons

Anti-amyloid fibril antibody [mOC87] - conformation-specific

ab201062

Frontal cortex plaques

Layer V cortical neurons (intracellular deposits)

Anti-beta amyloid 1-42 antibody [mOC98] - conformation-specific

ab201061

Frontal cortex plaques

Layer V cortical neurons (intracellular deposits)

Anti-amyloid fibril antibody [mOC116] - conformation specific

ab205342

Frontal cortex plaques

Layer V cortical neurons, hippocampal plaques

 

*14 month-old 3xTg-AD mouse model of Alzheimer's disease

** IHC shown in Hatami et al. 2014

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.
  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.
  17. McLean D, Cooke MJ, Albay R, Glabe C, Shoichet MS (2013). Positron emission tomography imaging of fibrillar parenchymal and vascular amyloid-ß in TgCRND8 mice. ACS Chem Neurosci 4, 613-23
  18. Nussbaum JM, Schilling S, Holger C, Silva A, Swanson E et al.(2012) Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-ß. Nature 485:651-5

About Abcam

Abcam is a global life sciences company providing highly validated antibodies and other binders and assays to the research and clinical communities to help advance the understanding of biology and causes of disease.

Abcam’s mission is to serve life scientists to help them achieve their mission faster by listening to their needs, continuously innovating and improving and by giving them the tools, data and experience they want. Abcam’s ambition is to become the most influential life science company for researchers worldwide.

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Last updated: Jul 14, 2018 at 6:33 PM

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