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

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.

We aim to establish the mechanistic and pharmacological basis of M1 mAChR-mediated modification of neurodegenerative disease by delivering on the following key objectives.

1. Full characterisation of the modification of prion disease mediated by M1 mAChR allosteric and orthosteric ligands.
This will involve determination of the biochemical, cellular, histopathological and behavioural impact of M1 mAChR ligands during prion disease progression from the on-set of the accumulation of misfolded prion protein through to end stage disease.

2. Establish the pharmacological and signalling basis of muscarinic modification of prion disease.
We will establish the pharmacological properties that define efficacy of M1 mAChR ligands, paying particular attention to the differential action of orthosteric agonists vs. allosteric modulators. We will also investigate the signalling pathways downstream of M1 mAChRs that mediate modification of prion disease and determine the impact of signalling basis.

3. Establish the molecular mechanism by which M1 mAChR ligands modify prion disease.
Using both a candidate approach and unbiased strategy as well as a system based techniques we aim to establish the mechanism of M1 mAChR drug action. This will not only include employing our expertise in biochemical techniques, including global proteomic and transcriptional analysis, but also involve engagement with our collaborators to apply neuroimaging, including fMRI and PET.

4. Determine if M1 mAChR-mediated neuroprotection in prion disease can be translated to AD using animal AD models, patient tissue and clinical data.
We will employ rodent AD models that show either tauopathy or accumulation of misfolded amyloid protein to evaluate the potential of M1 mAChR ligands to modify AD-like disease progression. Access to AD patient samples (through Eli Lilly) for pharmacological and signalling studies, and clinical neuroimaging data will ensure a translational focus to this programme.

Academic Beneficiaries - who they are and how will they benefit
There is considerable academic interest in defining new pharmacological intervention strategies to treat neurodegenerative diseases such as Alzheimer's disease (AD). Furthermore, there is general interest in developing approaches that employ animal models (genetic, chemogenetic and disease models) that can test the efficacy of drugs in the modification of neurodegeneration. This programme aims to address these issues; as such among the major beneficiaries will be the GPCR signalling and pharmacological communities, neuroscientists, research groups interested in employing chemical biology and chemogenetic approaches, and researchers that develop mouse genetic models to define in vivo signalling pathways. Specifically, the GPCR biologists and pharmacologists will benefit from the information gained, and the approaches and methodologies developed, to investigate the pharmacological and signalling properties of M1 muscarinic acetylcholine receptor (M1 mAChR) ligands that can impact on neurodegenerative disease. Furthermore, researchers focused on novel chemical biology tools and chemogenetic approaches will benefit from the methods and approaches employed in generating the muscarinic receptor chemical tool box and the design and use of the chemogenetic approaches such as DREADD receptors to defining the action of the M1 mAChR. Finally, the generation of genetic models to define receptor-signalling pathways that mediate the clinical end points of M1 mAChRs will provide a framework of methodologies that will benefit researchers interested defining signalling pathways in other biological systems.

Industrial Beneficiaries - who they are and how will they benefit
Our industrial partner, Eli Lilly, and other pharmaceutical companies interested in targeting AD, will benefit from our study that will investigate if the M1 mAChR is a valid target in AD. Furthermore, these companies will benefit from understanding the pharmacological and signalling properties of the M1 mAChR ligands that impart modification of neurodegenerative disease since this will inform their own rational drug design strategies. Furthermore, the general principles established in this study could be applied to other GPCR-based drug discovery programmes extending the impact of this programme to other disease indications.

Patient Beneficiaries - who they are and how will they benefit
The number of people worldwide with dementia is projected to rise to 65 million by 2030. First world countries are currently carrying a significant burden of disease with, for example, an estimated 10 million dementia suffers currently in Europe. However, it is predicted that over the next few decades, the burden of dementia will shift to developing countries where there is the fastest growth in the elderly population. These countries include China, India and countries in South Asia and the Western Pacific. In fact by 2050 people aged over 60 will represent 22% of the worlds population with four-fifths living in Africa, Asia and Latin America. Hence, morbidity and mortality resulting from dementia caused by neurodegenerative diseases such as AD will not only occur in the first world but also in lower and middle income countries. The need to discover novel treatments that slow or prevent neurodegenerative disease is therefore desperately needed for almost all nations of the world. By directly testing the clinical potential of targeting the M1 mAChR, this programme will significantly contribute to efforts to define novel treatments to diseases such as AD. Furthermore, the novel methodologies and approaches used in this study can be readily adapted to the investigation of the clinical potential of other targets in neurodegenerative disease thereby significantly extending the impact of this programme.