A New Method to Develop PET Ligands for Protein Aggregates in Neurodegenerative Disorders Using Soluble Brain-Derived Aggregates

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A common feature of all dementias e.g. Alzheimer's, Parkinson's and Huntington's diseases are the presence of specific proteins in the brain, which due to having abnormal structures, accumulate into increasingly large assemblies and fibrils. These structures, which are present in many regions of the brain, are considered to be toxic and damage brain cells, leading to the symptoms of dementia. Using the clinical brain imaging technique of Positron Emission Tomography (PET) combined with injecting into patients chemical probes, which selectively bind to these assembles, we can now visualize the presence and distribution of some of these toxic proteins. However, with the present range of these chemical probes we can only image the late stages of these assemblies when most of the brain damage has occurred and so too late for effective drugs therapies. Therefore, our aim is to develop a general method to find the next generation chemical probes that can image the earlier stages and structures of these abnormal proteins when they are considered most toxic and hence cause the most damage to brains cells. This would then create a powerful means for earlier more accurate diagnosis of dementia and a means of evaluating the new types of drugs that are been developed that target these assemblies. To do this we will extract small amounts of soluble toxic aggregates from samples of brain tissue from patients who unfortunately died with a neurodegenerative disease and directly image the binding of labelled probes to these aggregates, using a very sensitive fluorescence method that we have developed that can detect single aggregates. This method will directly test binding to the aggregates in humans and needs only very small amounts of reagents. Once we have probes that bind to the soluble aggregates we can see if other unlabelled potential probes can remove them and hence more rapidly screen for better probes that will work in humans and can be used to detect the aggregates formed at early stages of disease.