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Immunotherapy Against N-Truncated Amyloid-β Oligomers

  • Thomas A. BayerEmail author
  • Oliver Wirths
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Immunotherapy against aggregated proteins has received considerable attention in the field of neurodegenerative disorders, especially true for Alzheimer’s disease (AD), which is characterized by the presence of extracellular amyloid-Aβ plaques and intraneuronal neurofibrillary tangles consisting of tau protein. Numerous studies have demonstrated that the amyloid cascade triggers tau pathology, with tau being intimately involved in the molecular mechanisms leading to neuron death in AD. We and others therefore believe that Aβ is the trigger and tau is the executer of neurodegeneration. The nature of neurotoxic Aβ is still enigmatic, because amyloid-plaque structures that harbor high levels of Aβ are not correlating with the symptoms of AD, nor do they trigger neuron loss. New hypotheses have emerged trying to explain this conundrum. One is that amyloid plaques, although built as a consequence of high Aβ levels in brain, are acting as a waste bin, thereby keeping toxic Aβ aggregates locally fixed in a nontoxic form. Another hypothesis claims that intraneuronal Aβ aggregation triggers neuron loss and lastly many researchers believe that soluble Aβ aggregates of full-length Aβ1–42 are the major trigger for the amyloid cascade of pathological events. On the other side, Aβ1–42 has consistently been shown to aggregate fast into amyloid fibrils that are the building blocks of amyloid plaques while it should not be forgotten that full-length Aβ1–42 is a physiological peptide produced throughout our life-span. There is now increasing evidence that N-truncated Aβ variants represent better drug targets than full-length Aβ. Full-length Aβ peptides start with an aspartate at position 1 (Asp-1) and end with alanine at position 42 (Ala-42). In AD brain, two N-truncated species are especially highly abundant: Pyroglutamate Aβ3–42 (AβpE3–42) starts with a transformation of Glu to pyroglutamate at position three (pyroGlu-3), and Aβ4–42 starts with Phe at position four (Phe-4). In contrast to pan-Aβ antibodies or antibodies that recognize all forms of pyroglutamate Aβ3–42 those antibodies that recognize exclusively oligomeric forms of pyroglutamate Aβ3–42 and/or Aβ4–42 have a low tendency to detect amyloid plaques. Both variants form soluble aggregates, have a high aggregation propensity, and have toxic properties in cell culture assays. Once expressed in neurons in transgenic mouse brain, they induce massive neuron loss associated with behavioral deficits. Interestingly, only minor plaque load is seen in these models arguing for a toxic mechanism of soluble aggregates of pyroglutamate Aβ3–42 and Aβ4–42. Therefore, we believe that these oligomer-specific antibodies will provide excellent tools for drug development to fight AD.

Key words

Transgene model Plaques Pyroglutamate Abeta Abeta 4–42 Neurodegeneration Neuropathology Neuron loss 

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG)Georg-August-UniversityGöttingenGermany

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