This week’s Nature publication by researchers of Probiodrug AG and the University of Virginia has received broad coverage in the international media. In Germany and Austria, it made major news in TV (ARD, MDR, ORF) and radio stations (dlf, MDR, dradio), while in the US Rudy Tanzi, neurogeneticist of Harvard Medical School and an advisor on the Alzheimer problem to US-President Barack Obama, was quoted in ScienceNews as saying: “This opens up a whole new view of the disease.”
Alzheimer researcher Thomas Bayer, Professor of Molecular Psychiatry at the University of Goettingen added in MDR INFO that the publication was “a very important contribution”, demonstrating that very small amounts of pGlu Abeta were able to drag normal Abeta peptides along into the deadly cascade and that tau protein was essential for the toxic function.
Nature paper demonstrates that toxicity in AD is induced by pyroglutamate Abeta and is tau protein dependent
Pyroglutamate Ab (“pyroglu Ab”) a predominant, highly toxic fraction of Aβ found in the brains of Alzheimer’s disease patients, triggers the formation of toxic oligomers exhibiting prion-like behavior and initiating neurotoxicity via a tau protein-dependent pathway, thereby explaining the crucial role of such modified Aβ in the onset and spread of neuronal toxicity in Alzheimer’s Disease.
HALLE/SAALE, Germany, May 2, 2012 – Probiodrug AG (Probiodrug), a biotech company developing products for the treatment of neurodegenerative and inflammatory diseases with a particular focus on Alzheimer’s disease (AD), today announced its scientists and academics collaborators published seminal findings on the role of pyroglu Aβ in AD pathology in the May 2, 2012 online edition of the journal Nature (DOI: 10.1038/nature11060). The new findings add to the growing body of evidence that pyroglu Aβ plays a crucial role in the initiation of AD. In addition, the research results further elucidate the mechanism by which pyroglu Aβ triggers neuronal toxicity.
The data published today suggest that pyroglu Aβ co-aggregates with “normal” Ab peptides to form low molecular weight oligomers (LMOs), which are structurally distinct and far more toxic to cultured neurons than oligomers derived from normal Aβ. Moreover, the presence of the neuronal protein tau is essential for toxicity mediated by LMOs that contain pyroglu Aβ. The results have been substantiated in transgenic mice designed to express increased levels of pyroglu Aβ. In these animals, the pyroglu Aβ-mediated neuronal loss and gliosis was prevented, if tau expression was shut down. The study is supplemented by results published in the Journal of Neurochemistry. Here the Probiodrug researchers reveal, that the aggregation propensity is caused by the hydrophobic nature of pyroglu Aβ.
The scientists also were able to demonstrate that the cytotoxicity is propagated by a prion-like templating mechanism of Ab misfolding initiated by pyroglu Ab: even after strong dilution to a solution containing only 0.000625% pyroglu Ab, the mix after 24h developed enough toxicity to kill 50% of neurons treated with it.
“Forget Alzheimer’s” is the title and the message of a book by German journalist Cornelia Stolze who is claiming to tell the “truth about a disease which isn’t one” (Cornelia Stolze, Vergiss Alzheimer. Die Wahrheit über eine Krankheit, die keine ist, Köln/Cologne 2011: Kiepenheuer & Witsch).
The book is strongly criticizing the handling of dementia, in particular Alzheimer’s disease (AD) in today’s medicine, pointing out the lack of adequate diagnostics and therapies and contrasting this sad reality with the often exaggerated promises of imminent breakthroughs by experts.
Stolze starts by explaining that to date, it is extremely difficult to diagnose Alzheimer’s disease. Most claims about new methods to confirm a diagnosis or, even better, to predict the onset have turned out to be false. She also points out that about 50 diseases and at least 150 medications may cause dementia symptoms. She concludes that most physicians are overextended to differentiate and often too early and too easily put the patient down as having Alzheimer’s, thereby impeding a causal treatment and condemning the patient to unnecessary mental derangement.
Examples are cognitive impairments associated with dehydration and depression, but also a variety of drugs, in particular, if patients take cocktails of drugs prescribed by different specialists who neglected potential interactions and side effects. Complications during surgery or anesthesia, too, can cause dementia symptoms. Stolze summarizes that about 75% of all dementia diagnoses are false.
She also points out that most medications on the market for the treatment of AD are ineffective, do not provide causal therapy and may at best slow down disease progression for a limited period of time.
These chapters are a strength of the book and can be read as a roll call to relatives, patient advocacy groups and the health care system in general to raise awareness about the various forms of dementia and to demand better diagnosis and better drugs.
Stolze then tells the 1970s story of how Alzheimer’s disease was put on the agenda of the then newly founded US National Institute on Aging (NIA). Back then, little was known about Alzheimer’s disease, but using a fancy name describing a threatening disease was way more efficient in raising awareness and money from governments and private sponsors than by talking in general terms about senility or dementia.
Subsequently, Stolze’s story gets astray as she tries to convince the reader that AD has been and still is a mere invention by the medical industry, and that every scientific description of the disease – whether in terms of pathology, biochemistry or cellular and molecular biology – is full of errors, inconsistencies and contradictions.
The author makes no efforts to go into the details to substantiate this claim. As an example, Stolze writes that plaques – long viewed as the hallmarks of AD – can be found in the brains of mentally wide awake elderly as well. She ignores that this fact has puzzled researchers since long and that there is an explanation to it already: plaques in the brain of healthy people do have a different molecular composition than those in people with AD, in which they predominantly consist of a certain, very toxic variant of the A beta peptide. The details have been elucidated by researchers from the German biotech company Probiodrug, with the first publications appearing in the late 1990s. The hypothesis meanwhile has been confirmed independently by various research groups around the world and a first drug addressing the underlying mechanism already has reached clinical stage.
Moreover, Stolze completely ignores that there are inherited forms of AD such as Familial Alzheimer’s disease (FAD) or Early Onset Familial Alzheimer’s disease (EOFAD), uncommon forms of Alzheimer’s disease which usually strike quite early in life. They are inherited in an autosomal dominant fashion and the genes involved have been characterized years ago. Moreover, studies in these inherited forms have revealed further details of the pathophysiological mechanisms involved in AD in general.
Further parts of the book deal with selected German Alzheimer specialists and their connections to industry and politics, raising questions about conflict of interest disclosures. This is an ongoing debate in medicine in general, and Stolze seems to share the widely held beliefs in Germany that a researcher or medical doctor, who files for a patent, already has crossed the line to unethical behavior.
Most regrettable about the book is that it shakes the confidence in medicine of patients, relatives and people involved in the care of dementia patients without providing any valuable guidance what to do and whom to trust if a loved one is showing signs of confusion, disorientation or loss of memory.
During the upcoming World Alzheimer Day, the German MDR radio will feature the efforts by German biotechnology company Probiodrug to develop novel strategies for the treatment of Alzheimer’s Disease (AD). MDR’s FIGARO am Vormittag morning magazine will introduce the company’s hypothesis on the onset of Alzheimer’s Disease (AD) and highlight the latest research results published by Probiodrug and co-workers from German and US research institutions in the recent Journal of Neuroscience.
It is well known that the presence of so-called beta-amyloid (A beta) plaques in the brain is not necessarily correlated with the occurrence of AD. Probiodrug discovered that in AD patients, the core of the plaques is made form a certain variant of the A beta peptide which is more neurotoxic, less soluble and able to rapidly aggregate with modified and unmodified A beta. Further investigations revealed that this toxic variant is generated by an enzyme called QC (glutaminyl cyclase). QC is responsible for activating certain hormones and enzymes in the brain by modifying a certain chemical group in these molecules. If it starts acting on A beta, it produces the toxic variant. Probiodrug also has demonstrated in various experiments that it is possible to prevent the formation or spread of toxic A beta plaques by switching off the QC enzyme. The company therefore is developing drugs to inhibit the enzyme as a potential treatment strategy to either prevent the onset of AD or slow down the progression of the disease.