APP-BP1, The Cell Cycle, and Alzheimer Disease

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DESCRIPTION (provided by applicant): We have identified a cell cycle protein that interacts with the intracellular domain of the amyloid precursor protein (APP). This protein, APP-BP1, drives the cell cycle through the S-M checkpoint in dividing cells. Overexpression of APP-BP1 in neurons causes them to die. Notably, expression of familial Alzheimer disease (FAD) mutants of APP in neurons results in (1) an increase in expression of APP-BP1, (2) entry of the neurons into the S phase of the cell cycle, and (3) neuronal apoptosis. Furthermore, APP-BP1 is overexpressed in at-risk regions of AD brain relative to controls. APP-BP1 represents one of the first real "handles" for determining the mechanism behind the loss of cell cycle regulation and DNA replication that appears to occur in AD. We propose that the interaction of APP with APP-BP1 is important for normal brain function, but that the regulation of the interaction between the two proteins goes awry in AD, resulting in cell cycle regulatory failure in neurons. The following specific aims test this hypothesis: 1. We will begin to define the signal transduction pathway that is activated by interaction of APP-BP1 with APP, and whose abnormal activation may cause entry of neurons into the cell cycle, resulting in apoptosis. 2. APP-BP1 participates in a novel ubiquitination-related pathway involving the ubiquitin-like molecule NEDD8. We will use immunofluorescence and confocal microscopy to identify the subcellular structures in which APP-BP1, NEDD8, ASPP2, and other molecules in the ubiquitinylation-related pathway reside, in primary neurons in culture and in control and AD postmortem brains. 3. The data obtained from accomplishment of specific aims 1 and 2 will suggest specific consequences of perturbations of APP-BP1-mediated signaling that we might expect to observe in postmortem AD brain. We will test whether these predictions are correct.