New Alzheimer's target a Notch above the rest?

Researchers based at New York's Rockefeller University, US, learned that a protein called casein kinase 1 could slow the formation of beta-amyloid protein - the main constituent of the amyloid plaques found in the brains of Alzheimer's sufferers and thought to cause the debilitating effects of the disease. It is hoped the breakthrough will lead to Alzheimer's drugs with fewer side effects. Alzheimer's is an incurable, progressive brain disorder that causes dementia. Current treatments work to slow down the progress of the disease by blocking the formation of beta-amyloid protein. However, some of the enzymes responsible for this process are also responsible for cleavage of a protein called Notch, which plays an important role in the development of healthy brain cells. Inhibiting both can lead to drugs with severe side effects. Now, by targeting a different method of plaque formation, the research team believe drugs that target casein kinase 1 will have fewer side effects. "Studies of brain tissue from Alzheimer's patients have shown an increase in casein kinase 1 expression,"​ said Paul Greengard, head of the Nobel Prize winning Laboratory of Molecular and Cellular Neuroscience at Rockefeller. "We found that the key enzymes involved in beta-amyloid production – called BACE and gamma-secretase – were targets of casein kinase 1, so we investigated what role it might be playing." ​The scientists modified mouse cells to generate a form of casein kinase 1 that was always active and found that these cells produced more beta-amyloid protein than normal. Then, using three different types of chemicals, they blocked the protein from functioning. When they did this, they were able to reverse the production of beta-amyloid protein, without affecting the signalling of Notch proteins. Beta-amyloid protein is toxic to mitochondria found in cells and ultimately causes nerve cell death. This in turn causes the symptoms of the disease, including loss of memory, an inability to learn, make judgments and perform day-to-day tasks. "Numerous efforts have been directed at the development of drugs that inhibit gamma-secretase but there have been significant side effects in animal studies,"​ said Greengard. "Our hope is that this research might lead to drugs that don't have those problems,"​ he continued. Several other companies are also developing Alzheimer's therapies that don't target gamma-secretase directly. For example, Samaritan Pharmaceuticals developed caprospinol (SP 233), which is remarkable because the drug appears to not only block the formation of amyloid but also cause deposits already present in the brain to disappear. The company filed an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) last November. US pharmaceutical company Elan are collaborating with US pharma giant Wyeth to develop a drug, which aims to induce an immune response that clears beta-amyloid. The drug (ACC-001) is currently in Phase I clinical trials. France-based ExonHit Therapeutics is developing a drug that reduces amyloid plaque build-up through the production of a related blood protein. EHT 0202 has completed a Phase I clinical trial and is currently being assessed in Phase Ib trials. Last December, Genentech agreed to pay up to $300m (€228) to Swiss Biotech company AC Immune to licence antibodies developed by their SupraAntigen technology as potential Alzheimer's disease treatments. Spain's Neuropharma was recently given a 2006 Frost and Sullivan European Healthcare award​ for Excellence in Technology for its Alzheimer's research. The company is developing a technology that could lead to compounds with a novel mechanism of action and potential disease modifying capabilities in the field of neurodegenerative diseases.