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Food for Thought: Probiodrug’s Alzheimer Hypothesis Independently Confirmed
Two decades ago, it was discovered by the founders of German biotech company Probiodrug that the so-called amyloid beta peptides (Aβ) forming the notorious plaques in the brain of Alzheimer’s Disease (AD) patients are not a homogeneous species. While it was known that there are variants in length (from 36 to 43 amino acids), the Probiodrug researchers discovered that there also are pyroglutamated variants (pGlu-Aβ) of the peptides. However, little was known about their origin and biological role. This has changed significantly over the last years, and Probiodrug has pioneered this research.
At this year’s 10th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2011), taking place in Barcelona/Spain from March 9 to 13, more than two dozen posters and presentations provide further insights into the mechanisms and consequences of pGlu-Aβ formation, and there is overwhelming evidence that pGlu-Aβ is key to understanding Alzheimer’s Disease and to developing novel treatments. Abstracts can be found here.
The findings can be summarized as follows:
1. Amyloid plaques alone correlate poorly with the severity of AD.
2. The presence of pGluAβ in plaques, however, does correlate with disease severity in both sporadic and familial AD.
3. Antibodies recognizing oligomeric forms of pGluAβ bind to plaques in the brains of familial AD patients.
4. pGluAβ is elevated 8.5-fold in AD brains compared to controls.
5. pGluAβ forms the center of plaques, with full-length Aβ at the periphery, suggesting that pyroglutamate forms Aβ seed deposits.
6. pGluAβ is a form of Aβ that aggregates faster than conventional full-length Aβ, is more neurotoxoc and – being protected against degradation – much more stable.
7. pGluAβ is formed by the enzyme glutaminyl cyclase (QC) at the N-terminus of Aβ by cyclizing a glutamate residue.
8. Expression of QC is increased in the brain of AD patients.
9. Mice engineered to express human QC show highly increased levels of pGluAβ as well as motor and memory problems.
10. QC not only produces pGluAβ, but also promotes inflammation by acting on monocyte chemoattractant protein (MCP-1, also known as CCL2), making a pyroglutamate derivative that is stable and resists proteases.
11. Mixtures of pGluAβ and conventional Aβ42 are 10- to 50-fold more deadly to neurons than either peptide alone.
12. Toxicity of these Aβ mixtures depends on the presence of tau, suggesting that tau acts downstream of Aβ.
Novel insights to the hypothesis presented on this year’s AD/PD 2011 include the discovery that QC enzymes are also responsible for the activation of several pro-inflammatory chemokines in the brain by introducing a pGlu-residue. As this residue confers resistance to proteolytic degradation, overexpression or -activity of QC may be involved in turning inflammatory processes into a chronic state of neuroinflammation, which often is observed in CNS diseases.
Another abstract describes a novel ELISA test for the reliable determination of Aβ in biological fluids as well as a novel antibody detecting the biologically active form of an inflammatory biomarker. The ELISA test allows for a clear discrimination between controls showing normal aging and individuals affected by Alzheimer’s Disease in prodromal or demented stages.