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The role of presenilin gene 1 mutations in Alzheimer's disease
Lane Simonian
Posted: Wednesday, March 4, 2015 10:22 PM
Joined: 12/12/2011
Posts: 5158

Presenilin gene 1 mutations are one of the main causes of early onset Familial Alzheimer's Disease. A recent study links these mutations to a loss of function rather than a gain of function.

For the first time, a study reveals exactly how mutations associated with the most common form of inherited Alzheimer's disease produce the disorder's devastating effects. The paper upends conventional thinking about the effects of Alzheimer's-associated mutations in the presenilin genes and provides an explanation for the failure of drugs designed to block presenilin activity...

"This paper clearly shows that these FAD mutations cause a loss of presenilin function and gamma secretase activity, leading to the loss of neurons in the adult brain," says Shen. "The most important implication of our findings is that strategies that enhance rather than inhibit gamma secretase should be investigated as potential Alzheimer's therapies. They also may explain why a major clinical trial of a gamma secretase inhibitor failed to help patients and actually worsened their cognitive abilities."

Individuals with presenilin gene mutations lack leucine which reduces gamma secretase activity via g protein-coupled receptors but also cuts off the neuroprotective phosphatidyinositol 3/Akt activity.

Gamma secretase inhibitors increase peroxynitrite formation while reducing hydrogen peroxide formation. The former kills neurons while the latter only damage neurons. Thus, medications attempting to inhibit gamma secretases make Alzheimer's disease worse. Alzheimer's progresses not because of the increase in gamma secretase activity but in spite of it.

Posted: Tuesday, March 31, 2015 9:45 AM
Joined: 3/31/2015
Posts: 4

Sounds interesting. I wonder if there is a test for these gene mutations?
Lane Simonian
Posted: Tuesday, March 31, 2015 10:18 AM
Joined: 12/12/2011
Posts: 5158

Welcome, sinnweja. There are genetic tests for these mutations.
Posted: Friday, April 10, 2015 7:45 PM
Joined: 12/6/2011
Posts: 3326

Hi, Lane. It's been a while since I've posted on these boards and still disappointed about the clumsiness of this site. I'm continue to be doing great and spending most of my time on advocacy. Was fortunate to have dinner with Sen. Patty Murray and 6 others, Including CEO Harry Johns and Dr. Dean Hartley. She is on a couple of Senate subcommittees dealing with Health and I believe she came away with a better understanding of the consequences if a cure or something to stop the progression doesn't come along.
Lane Simonian
Posted: Friday, April 10, 2015 8:38 PM
Joined: 12/12/2011
Posts: 5158

I am really pleased to see you posting again, Myriam. I was sorry to see us lose great people due to the problems with the new website.

I am happy that overall you are doing well. You are such a good advocate. I just like the idea of Senator Patty Murray listening carefully to the knowledge and urgency that you and all the others at the table were able to impart to her. From all I know of Patty Murray she is going to utilize what she learned that night for the good.