Separating cell-autonomous from -extrinsic effects of APP/Ab
The amyloid precursor protein and its derivative, amyloid beta, are intimately associated with the onset and progression of Alzheimer's, yet there are still many basic questions about their role in neuronal dysfunction that remain unanswered because we lack appropriate model systems in which to address them. We are investigating a new viral mosaic APP" transgenic mouse model that allows us to tackle fundamental questions about whether APP and amyloid beta act locally in a single cell or exert their effects between cells to alter neuronal structure and function. We are exploring whether their overexpression in the mature brain has distinct effects from those effects that might be seen during early embryological and post-natal development. Answers to these deceptively basic questions will be critical to understanding how APP/amyloid beta contributes to Alzheimer's pathogenesis and determine how best to target its action therapeutically."
Our study is designed to address a fundamental question in Alzheimer's research: are nerve cells in the brain being killed by murder or suicide? Restated, are neurons succumbing to the effects of proteins that they make themselves, or are they being damaged by protein made by their neighbors? This simple question is surprisingly difficult to address. The transgenic mice commonly used to study the effects of Alzheimer's disease-associated proteins in the brain cannot distinguish whether neuronal damage starts from within the cell or from outside because all of the neurons in these mice make the same proteins. Yet we will need to find the answer to this question in order to design future therapeutics that get to the right place and inhibit the correct target. We are taking advantage of newly developed technology to create a mouse model that will allow us to separate these effects by expressing the disease-related protein in a mosaic pattern within the brain. In this model some cells will carry the protein while others will not. We can then test which population of cells becomes sick -- those with the protein or their neighbors. Answers to this question will determine whether we're looking at a murder or a suicide. In addition to this spatial control over protein expression, the mice also carry a gene that allows us to determine when the Alzheimer's-related protein is active. This feature will help us to determine whether the Alzheimer's-protein acts in the same way in young neurons as it does in mature ones and ensure that changes we ascribe to the disease are not influenced by damage caused by exposure to the protein during development of the brain. Dr. Jankowsky's expertise in developing new mouse models for Alzheimer's disease, and her collaborator's experience with the study's viral technology, are perfectly suited to the challenges of developing this much-needed experimental system. When completed, we will have created the first controllable mosaic transgenic mouse model for Alzheimer's disease, and will have answered several fundamental questions about where and when Alzheimer's-related proteins damage the structure and function of neurons to cause the disease's devastating cognitive symptoms.