A Molecular Basis for Selective Neuronal Vulnerability

Principal In Alzheimer’s disease, as well as in other neurodegenerative diseases, specific areas of brain cells are affected in virtually every case, whereas other areas of brain cells appear to be unaffected in virtually every case. These striking differences have been referred to as “selective vulnerability” and, although this phenomenon has been well known for many years (for stroke and other insults, as well as degenerative diseases), it is not understood. It is an important finding because it shows that some brain cells can live very successfully during a neurodegenerative disease such as Alzheimer’s disease, whereas something renders other cells very sensitive to the disease process. If the differences could be discerned, this might suggest new treatments: for example, a drug might be added that would make the sensitive cells more like the resistant cells, or would block whatever is causing the sensitive cells to be sensitive.

My colleagues and I have discovered two different molecules on the surface of brain cells that make the brain cells sensitive to a number of different insults. One of these makes the brain cells sensitive to ß-amyloid peptide, and happens to be produced almost exclusively by those cells that have been known for years to degenerate in Alzheimer’s disease. Thus, we believe that this “suicide molecule” may underlie the· selective vulnerability of the cells that produce it to death in Alzheimer’s disease. We are currently evaluating this using transgenic mice, mice which have many copies of the suicide gene, and knock-out mice, which have no copies of the gene.

One might ask why humans carry molecules in our brains that are designed to kill the brain cells under certain circumstances, and the answer is that we don’t know, although we speculate that this may be important in allowing certain cells to live and others to die during the formation of new connections, for example related to memory. We believe that it is very important to understand the method used by this interesting suicide gene to bring about brain cell death. If we understood this, we might be able to design therapeutic agents to prevent the neural cell death. Recently, Dr. Barbara Chapman found that a related molecule, which functions primarily outside the nervous system, has a remarkable similarity to the brain cell suicide molecule in the very area of the molecule which appears to be required to induce the suicide of the cells. Therefore, the findings from the molecule outside the brain give us a head start on understanding the suicide receptor that functions in the brain. To further our understanding of the suicide molecule, we first plan to make very minor but very highly directed changes at critical points within the part of the molecule that induces death, because these will show whether or not our model of the method of death induction by this molecule is appropriate. Next, we will introduce systematic changes to understand what turns the killing on and what turns the killing off, since this molecule has the interesting property of being “on” all of the time unless it is switched off by another molecule. Third, we will evaluate chimeric molecules that will reveal whether the turning off of the death is accomplished by dimerization, that is by bringing two molecules together to shut each other off. Fourth, since the structure of the molecules predicts an interaction with a specific type of mediating protein, we will evaluate this possibility by measuring levels of a cellular compound referred to as cyclic AMP. Finally, although it is outside the scope of the current proposal, we are attempting to find what proteins interact with the death molecule to carry its signal to the heart of the cell.

We believe that the understanding of selective vulnerability in certain populations of brain cells will lead to a better understanding of the process of Alzheimer’s disease, as well as a better understanding about therapeutic targets.