New Direction in Alzheimer’s Research

In the laboratory of Nobel laureate Dr. Paul Greengard, a team of researchers is looking into a new direction in research into the nature of Alzheimer’s disease. Preserving Your Memory talked to Jean-Pierre Roussarie, Ph.D., postdoctoral associate at the Fisher Center for Alzheimer’s Research Laboratory, about the work they’re doing now.

Preserving Your Memory: Please tell me about the research you’re currently doing in Dr. Greengard’s lab. What is the nature of the research? What are you targeting?

Jean-Pierre Roussarie: Some regions of the brain are very clearly more vulnerable than others to Alzheimer’s disease. In these regions neurons are starting to malfunction and then die at very early stages. Later on during the course of the disease, neuron death becomes more widespread across the brain. From one patient to another, neurons from the same region—namely the hippocampal formation, the region involved in new memory formation— die, and this is a very reproducible process. is is why the disease is so circumscribed to problems in forming new memories at the beginning. Until now, it’s been a mystery why these neurons are so vulnerable while others are not aected until very late stages of the disease. So we want to understand what these cells have in particular that makes them so sensitive.

What we’re doing is this: e lab set up a new technology to isolate material from any given neuron of the animal model and analyze in a very comprehensive way all the proteins that are present in these cells. We are applying this technology to Alzheimer’s disease to isolate material from the Alzheimer’s disease vulnerable cells and from more resistant cells. By comparing the proteins present in either vulnerable or resistant cells, we can try and pinpoint what makes a cell vulnerable or resistant to the disease.

PYM: What results have you discovered thus far from your research, or what do you expect to find?

JPR: It is a very, very long project. In order to apply this technology, which is very new (the lab invented and published it 3 years ago), we need to set up tools beforehand. For each brain region that we want to analyze, we need to “construct” a specialized animal model that we are going to isolate material from. I’ve been working in the lab for a few years, and we are really just starting to collect results. We soon expect to be able to compare vulnerable and resistant neurons, and to look for differences between these neurons. A protein that is present in all vulnerable neurons but not in resistant neurons might be a protein that makes neurons more vulnerable, and trying to counter its eect might be a very promising therapeutic avenue. On the contrary, a protein present in all resistant cells but not so much in vulnerable cells, might protect resistant cells against the pathology. Trying to potentiate its eect in vulnerable cells might prevent them from dying. The general idea is thus to try to find a way to make a vulnerable cell more resistant.

PYM: What impact might your work have on Alzheimer’s diagnosis or treatment in the future?

JPR: Since the failure of clinical trials that were carrying a lot of hopes in the field, like the Semagacestat trial, the Alzheimer’s disease researchers are looking for new directions. Ours is definitely a very new direction. People haven’t looked so much at why the disease affects just one region of the brain, just because no technique was available to do so in a very precise manner. Neurons are very different from one region to the next, and it’s important to focus on the particularities of these neurons that are the key actors of the disease.

We hope to nd ways of treating these vulnerable cells, to prevent them from dying. If we can make a vulnerable cell more resistant by correcting what makes it vulnerable, we can imagine intervening in Alzheimer’s disease patients at early stages of the disease to prevent vulnerable cells from dying in their brain.

PYM: What directions can you see your work taking in the future?

JPR: e whole beauty of the project is to be able to not make any hypothesis. Science has long been about making a hypothesis about a disease mechanism and trying to prove it with experiments. We are analyzing the dierences between vulnerable and resistant cells in a very comprehensive manner. So we don’t have to hypothesize. Our results will tell us in what direction to go. So it is very hard to predict what directions it will take.