The role of over-activation of the endocytic pathways in the neurodegeneration observed in Alzheimer’s Disease. Alzheimer’s Disease (AD) is a neurodegenerative disease leading to a progressive destruction of brain cells and decline in mental function. AD affects the individual’s ability to remember, judge, learn, and carry out daily activities. It is estimated that up to 4 million people suffer from the disease, and the annual national cost of care is estimated at $50 billion. Given the debilitating effect of the disease on a personal as well as on a national level, research leading to new and effective treatments for the disease is much needed. It is my belief that each new line of research brings us closer to finding that treatment.
Two key discoveries initiated the research I’ve conducted with the help of the Rappaport Foundation. The first is that one of the earliest abnormalities in brains of individuals with AD is found in their endosomes, which are the structures that enable substances to enter cells and circulate from one structure to the other. The second discovery is that AD involves pathways that can lead to a specific form of cell death called apoptosis, the genetically programmed cell death that limits cell life span, which may be regulated through the amyloid precursor protein (APP), the source of the brain plaques that are the hallmark of AD.

I hypothesized, based on these and other findings, that the interaction between APP and APP-BP1, which is an APP binding protein, may normally play a role in endocytosis, and when APP signaling goes awry, as we hypothesize happens when genetic Alzheimer mutations of APP occur, the interaction between the two proteins leads to over-activation and sustained stimulation of the endocytic process. This over-activation could play a role in the brain changes observed in AD.

During the course of the study I was able to show ways to rescue neurons from death by changing the activity of endosomal proteins along this pathway that is activated by interaction between APP and APP-BP1. The significance of these findings is two-fold. On the one hand, it validates previous findings of endosomal abnormalities in AD as being part of the causal chain of events leading to neurodegeneration, and on the other hand, it suggests that intervening in those steps in the pathway resulting in abnormal endocytosis may positively affect the fate of neurons in the disease. I was able to show further the specificity of the pathway, by demonstrating that blocking other proteins involved in endocytosis does not inhibit the cell death.

Through further data collection and research into the causes and potential prevention of cell death, my work as a Rappaport fellow has had significant implications in terms of our understanding of the processes of neurodegeneration occurring in the disease. My work shed light on one of the missing pieces of the puzzle in AD – the connection between abnormal processes of endocytosis and signaling through the APP pathway.

Not only did my experiments yield promising results, but this fellowship enabled me, within one year, to successfully develop this new field of research in AD. In addition, as a result of the data obtained and the further hypotheses stemming from it, I am seeking further collaborations with scientists in the Boston area focusing on different aspects of AD in order to assume a more integrated approach toward research in AD. This research has given me the opportunity to broaden my scientific knowledge as well as my methodological expertise, and has motivated me to proceed and further elaborate on this particular research project.