Grant: Project Grant

New evidence from human brains reveals that the earliest sign of the possible development of Alzheimer's Disease is the appearance of a protein called pretangle tau in brainstem neurons even at young ages. In older brains one of the major signs of Alzheimer's Disease is tau tangles and this pretangle tau is its precursor. Over years pretangle tau spreads from the brainstem neurons to other neurons, finally appearing in most of the brain's cortical neurons in advanced Alzheimer's Disease. We have used gene insertion techniques to put pretangle human tau into rat brainstem neurons. In this experimental model, the human pretangle material spreads from brainstem neurons to other brain areas over time as has been described in humans. Pretangle tau rats also develop odor discrimination problems later in life as reported in humans who are likely to go on to experience more severe memory loss. Inserting pretangle tau in the brainstem neurons of middle aged rats produces worse effects. In a shorter time they begin to lose neurons and have severe learning problems. Now we want to know how pretangle tau changes neurons at first and over time. We will look at the brainstem neurons where Alzheimer's Disease begins and at the cortical neurons needed for olfactory discrimination and for life memories. We will use electrophysiology and genetic methods to learn how pretangles change neuron function over time and we will try to identify therapies by which negative changes can be prevented. We will also test the hypothesis that pretangle tau changes its structure in a small way before it becomes toxic to neurons and that preventing this change in pretangle tau structure can prevent the bad effects of pretangles and prevent the development of Alzheimer's Disease.