MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.

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Dementia is currently one of the major global health challenges. In Europe alone, dementia resulting from neurodegenerative diseases, such as Alzheimer's disease, is projected to rise to 14 million by 2030 - a trajectory that will make dementia second only to cancer as a cause of morbidity in the first world (1). Dementia is not, however, limited to the world's wealthiest countries. The most dramatic increases will be in developing countries including China, India and countries in South Asia and the Western Pacific, where there is the fastest growth in the elderly population. Unlike many other global health challenges, such as malaria, HIV and TB, there are currently no treatments available that slow or prevent the progression of neurodegenerative disease. Furthermore, the pipeline of drugs in development and undergoing clinical testing are alarmingly small. There is therefore an urgent global need to develop new drugs that slow or prevent the progression of neurodegenerative disease. This grant directly addresses this question. We have found that by activating a specific brain protein we can slow the progression of a neurodegenerative disease in mice. This disease is called murine (mouse) prion disease and is similar to human Creutzfeldt-Jakob disease otherwise called CJD and mad cow disease. We have discovered that drug like molecules that bind to and activate a protein called the M1 muscarinic acetylcholine receptor can slow the progression of prion disease in mice, thereby extending their life. This grant is aimed at determining how the activation of this receptor protein can slow disease progression and how best to design drugs to activate this receptor protein. We will then test if the ability of the drugs we discover to slow prion disease can also slow other types of neurodegenerative disease, including Alzheimer's disease. In this way this grant will establish the principles that can be employed to make drugs that slow or even stop neurodegenerative diseases in people.