Tag: Alzheimer’s disease

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.

 

Food for Thought: Weekly Wrap-Up

Electronic waste is proliferating at an incredible speed: In 2007, an estimated 40 million computers became obsolete world-wide and the rapid turnover of cell phones, printers, cameras etc. comes on top. A US-solution to the problem is introduced by William Pentland in Forbes this week: EcoATM, a California-based startup, provides self-serve electronic recycling stations, or “ecoATM kiosks” at shopping malls, supermarkets and other high-traffic areas. Consumers can insert cell phones they want to get rid off and immediately get a quote based on the value of the device in secondary markets. The business model is about to be expanded to additional portable devices.

Rainer Floehl in Frankfurter Allgemeine Zeitung (FAZ) explains that to date, leukemia diagnostics does not take important informative parameters into account. A study in about 1,400 patients with acute myeloid leukemia (AML) led to the development of a risk scale which was subsequently tested in a further 800 patients. The scale comprises factors like patient age, chromosomal changes and body temperature as well as concentration of thrombocytes, hemoglobin fibrinogen and lactate dehydrogenase enzyme. The new scale will allow to stratify patients for aggressive chemotherapy or milder forms of treatment, thereby reducing unnecessary, severe side effects.

Alexander Picker, David Jackson and Stephan Brock in Die ZEIT respond to an article by Martina Keller in the same paper published in January, which dismissed the majority of novel cancer drugs as providing only marginal benefit to the patients while being grossly overpriced and full of severe side-effects. The authors, biologists and managers of Life Biosystems AG (Heidelberg, Germany), a company developing decision support systems for oncologists, point out that judgements like this – frequently found in today’s media – do not take into account the progress which is currently being made with personalized cancer therapies. They state that the diagnostic and analytic advances in this field still have to reach clinics and patients as well as regulatory agencies and insurers.

Malcolm Ritter in Die Welt reports about progress in personalized prostate cancer therapy. To date, a lot of men receive over-therapy such as chemo- and radiotherapy because doctors cannot tell apart aggressive from slowly growing, more benign forms. The article introduces a test developed by Ronald DePinho of Dana Farber Cancer Institute which identifies aggressive forms.

Alexander Wehr in Die Welt reports about a paradigm shift in preventing stroke by using novel anti-coagulants such as apixaban, dabigatran, edoxaban and rivaroxaban instead of warfarin or aspirin. In the same paper, Maria Braun features a study conducted by the University of Toronto showing that bilinguality has a surprisingly high protective effect against Alzheimer’s disease.

Finally, Amy Wallace in the New York Times introduces a start-up still seeking investors that has taught parasitic wasps new tricks. The founders discovered that wasps can be drilled to sniff any volatile substance, even if it is not occurring in the wasps’ natural habitat, and that they are even better in detecting odor traces than dogs. First product of the newly founded company is a device for detecting bedbugs, but the founders think of other applications as well – from sniffing explosives to detecting drugs or cadavers. The company is seeking a modest $200,000 to get the prototype on the market.

Company News: Probiodrug to Host Alzheimer Symposium

Despite considerable efforts to find a cure, Alzheimer’s disease  (AD) at present cannot be treated adequately, as there is no therapy available to significantly slow down disease progression, halt the disease or prevent it.
During the past years, researchers from the German-based biotech company Probiodrug have generated a compelling body of evidence that a particular variant of the notorious A beta peptide, which clumps together in the brain of AD patients to the typical plaques, is the major culprit. This variant is formed through a hitherto unknown reaction of a brain enzyme called glutaminyl cyclase (QC) and carries a pyroglutamic residue at its N-terminus. This renders it much more neurotoxic than the unmodified A-beta and also significantly reduces its solubility so that it starts aggregating.
Today, this hypothesis  is not an outsider opinion any more. On Monday, November 22, well-known Alzheimer researchers from Germany (Christian Haass, Stephan v. Hörsten, Marcus Fändrich, Thomas Bayer, Steffen Roßner, and Stephan Schilling), the U.S. (Cynthia Lemere, Lennart Mucke, Steve Jacobsen), Austria (Reinhold Schmidt), and Japan (Takaomi Saido) will meet at Probiodrug´s Halle (Saale) headquarter to provide the latest findings in the light of this hypothesis and to discuss novel therapeutic strategies. One of the approaches pursued by Probiodrug is inhibiting the formation of the toxic A-beta variant by small molecule inhibitors of the QC enzyme.
The public symposium entitled “Neurodegenerative Disorders During Aging – Contemporary Research and New Therapies” will take place on Weinberg Campus in Halle (Saale) on Monday, November 22, 2010, from 10am to 3pm. The detailed program can be found on Probiodrug‘s website.

Food for Thought: Key to Stopping Alzheimer’s Disease

In Germany, newpapers are widely reporting about a recent paper by a team of researchers led by  Thomas Bayer from Ernst-August University Goettingen, Germany, in which the team reports about an approach able to halt the progress of Alzheimer’s disease in mice.

For a long time, researchers have tried to stop Alzheimer’s disease (AD) by either dissolving the plaques found in the brains of AD patients or by trying to get rid of the so-called Abeta peptide that is believed to aggregate to plaques. However, none of these approaches has been successful so far.

A couple of years ago, researchers from the biotech company Probiodrug AG (Halle, Germany) found that the major culprit for the detrimental aggregation of peptides to plaques is not Abeta as such, but a variation carrying a pyroglutamate residue. This pyroglutamated Abeta peptide (pGlu-Abeta), they found, is generated by a hitherto unknown reaction catalyzed by the brain enzyme glutaminyl cyclase (QC). pGlu-formation leads to stabilization of the peptide and protection against cleavage. Moreover, Probiodrug has been able to demonstrate that pGlu-Abeta peptides show increased neurotoxicity, a prolonged half-life and an increased tendency for aggregation. They also form the seeds of the typical plaques observed in the brain of AD patients.

While Probiodrug is developing small molecule inhibitors of the QC enzyme to halt the disease, Thomas Bayer (who is a member of Probiodrug’s Scientific Advisory Board) and his team generated a monoclonal antibody against pGlu-Abeta. Passive immunization of transgenic mice models of AD  with this monoclonal antibody significantly reduced overall Abeta plaque load and levels of pGlu-Abeta, and also normalized behavioral deficit in the mice.

Later this month during the Neuroscience 2010 conference, Probiodrug will demonstrate that increasing pGlu-Abeta potentiates the behavioral deficits observed with transgenic AD mouse models significantly, and will also presented data showing that inhibitors of QC can reduce the level of pyroglutamated beta-amyloid species and alleviate the observed behavioral changes.

While the approach presented by Thomas Bayer will take a few years to reach the clinic, Probiodrug’s first small molecule QC inhibitor already has reached the regulatory phase.

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