Applying the 3Rs to elucidate the mechanisms of tau pathology using DRG neurons in culture

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Nerve cells are complicated highly branched cells that are essential for our brains and our bodies to function. Without nerve cells we cannot think, feel, walk, pump blood or digest our food. The protein tau is a nerve cell protein that enables neurons to distribute essential proteins to distant parts of the cell in the brain, spinal cord, and in neurons that mediate sensation and control the actions of our internal organs. In Alzheimer's disease, tau ceases to function normally; it becomes misfolded and eventually forms neurofibrillary tangles (NFT) that are thought to be critical for neurodegeneration in the disease. Currently there are over 20 different human neurodegenerative diseases that show NFT, some of which are caused by a single mutation in the gene that codes for tau. This observation demonstrates that mutant forms of tau are enough to cause neurodegnerative disease. However, in many cases tau is not mutated, yet it still forms tangles. Tau is therefore an important therapeutic target. Quite a lot is known about pathological changes that occur in tau but one fundamental problem is still unanswered: what form of tau is truly pathological and how tau causes the nerve cells to die? These problems are difficult to solve by looking at the nervous system in post mortem human brains because it is difficult to catch a dying nerve cell as dead nerve cells are rapidly cleared by neighbouring cells. For this reason mouse models of tauopathy have been created where several features of the disease are replicated. However, even in mice, the dying cells in the brain are not easily accessible. To reduce animal use and still be able to investigate how tau kills cells, we have turned to a cell culture system of nerve cells from the sensory nervous system. What is intriguing is that the neurons that are cultured develop aspects of tau pathology as time goes by. Moreover, those nerve cells that express pathological forms of tau go on to die. This allows us to gain access to individual nerve cells to study the causes and mechanisms of tau pathology. and at the same time, reduce, refine, and replace a large number of mice that would have been otherwise necessary for this study. We now know that cell death is not necessarily a random process. It can involve the orderly demolition of the cell. Here we propose to develop this model to determine the pathways by which tau causes nerve cell pathology and death. We also wish to explore whether we can keep the sick nerve cells alive using drugs that are being developed for eventual use in humans. And, importantly, this model will reduce use of mice in research aimed at solving the mystery of why tau disables nerve cells and causes them to die.