Interaction of Alzheimer's Presenilin-1 and Presenilin-2 with Bcl-X_L

Passer, B.J. et al. (1999). Journal of Biological Chemistry 274: 24007-24013.

In this paper, the author's are trying to understand how proteins involved in the development of Alzheimer's disease may regulate cell death (since many cells die during the progression of this disease).  So, what are the presenilins?  Well, about 10% of the cases of Alzheimer's are familial (call FAD, Familial Alzheimer's Disease), which means that genetics plays an important role (the other 90% are more likely due to exposure to toxins in the environment or other non-genetic causes).  Now, in FAD, many of the mutations occur in the genes encoding presenilin-1 (PS1) and presenilin-2 (PS2).  It is currently thought that these mutant presenilins then give rise to the neurotoxic form of beta-amyloid (beta-amyloid-42/-43).  You may have heard of the beta-amyloid plaques that are a pathologic hallmark of Alzheimer's.  Well, these are caused by the neurotoxic forms of beta-amyloid. 

Interestingly, it seems that the presenilins may also play a role in regulating in cell death via another route as well!  In this paper, it was found that PS1 and PS2 can bind to an important survival protein called Bcl-XL (you can check out my Bcl-2 website for more detailed information!).  Let me just say that Bcl-XL is a survival protein because it protects the cell from cellular suicide (called apoptosis, again, you can check out my apoptosis website for more detailed information regarding this exciting area!).  The author's determined that although both the normal and mutant presenilins both bind to Bcl-XL, the effects are quite different.  Importantly, when the mutant presenilins (that are found in FAD) bind to Bcl-XL, they disrupt the ability of Bcl-XL to protect the cell from apoptosis!

Now, this section isn't too hard, so shouldn't be too long.  Alzheimer's is a devastating disease that leads to senility.  Alzheimer's is characterized by three major pathologic hallmarks: beta-amyloid plaques, neurofibillary tangles, and neuronal cell loss.  However, the causes of Alzheimer's are still quite unclear.  At least in FAD, the presenilins seem to play an important role.  One, they can lead to the production of the neurotoxic forms of beta-amyloid (leading to plaque formation) and two (from this paper) may sensitize the neurons to apoptosis (which may in part help explain the neuronal cell loss).  As we better understand the functions of the proteins involved in Alzheimer's, we can begin to develop more effective therapies to help individuals with this terrible disease (hmmm...I sound like a marketer from a pharmaceutical company, don't I?  Sorry!).

Anyway, I hope you enjoyed this brief summary, and I hope you'll check back soon for more recent advances!  Thanks!