Fundraising appeal from Dr. Mahley at Gladstone Institutes

[Julie G]

ApoE4.Info, Inc. will occasionally pass along fundraising requests from researchers when their mission aligns with ours. Such is the case with the work done by the folks at Gladstone Institutes. You can read about the ApoE4 structure corrector they’ve developed here. Please see a letter from Dr. Mahley written specifically to our group with an update on the structure corrector followed by a PDF that describes Gladstone's current campaign. If you’re so inclined, feel free to directly support their research. 

Dear Julie,

Greetings from San Francisco. I am writing for two reasons. First, to update the ApoE4 community on our progress in developing a therapy to prevent/retard the detrimental effects of apoE4 in Alzheimer’s disease (AD.) Second, to seek the help of the apoE4 community in securing funding for the Gladstone Institutes to much a unique opportunity that we have to support our AD program. If you are willing, I would appreciate it if you would communicate my letter and the one attached to the apoE4 group. As you will see, a major supporter of the Gladstone has pledged up to $1 million to match gifts coming from others, dollar for dollar. This could have a major impact on our AD research.

Significant progress has been made in identifying compounds (hopefully a drug) that converts the abnormal structure of apoE4 to a normal form and in so doing prevents/retards the detrimental effect of apoE4. The biotech company, E-Scape Bio, Inc. is advancing this work. We now have potent molecules that reverse the effects of apoE4 in nerve cells and mouse models.

Personally, I remain at Gladstone Institutes and continue my work designed to complement the structure corrector program. My work attacks this problem by understanding how apoE4 impairs energy production in nerve cells by poisoning an organelle called mitochondria- the powerhouse of nerve cells. This represents an approach to boost the effects of an apoE4 structure corrector drug. We are working hard to advance these studies.

The support of the apoE4 community will make a significant difference. I hope the community will consider joining us in our endeavor to fund this vital program.

Best regards-

Bob Mahley

RWM letter to Julie Gregory_attachment2.pdf

And, as always, you may donate to ApoE4.Info, Inc. by visiting this page.

[Julie G]

Friends, I just received an update from Dr. Mahley regarding the current focus of his research. Given Gladstone Institute's ongoing fundraising appeal, I decided it was most appropriate to share in this thread:

Greetings! I would like to update the ApoE4 Community on the latest research on apoE and Alzheimer’s disease at the Gladstone Institutes.

As illustrated in the figure, one of the major pathways whereby apoE4 impairs nerve cell function and adversely alters memory is caused by the abnormal structure of apoE4 (compared to apoE3 and apoE2). I previously shared with the group that one small change in the sequence of apoE4—one amino acid out of 299 changed—profoundly alters its structure and causes apoE4 to be recognized as abnormal in cells that make it, such as injured or stressed nerve cells. This causes the structurally abnormal apoE4 to undergo cleavage by a protease that generates a series of neurotoxic fragments. These fragments can move throughout the cell and injure or impair normal cellular functions, thus damaging the cells. One component of nerve cells that is damaged is the mitochondria—known as the powerhouse of cells that is responsible for energy (ATP) production to maintain the life of the cells. The apoE4 fragments directly bind to the mitochondria and this interaction alters their normal function.

09.268A11.jpg

As you know, we are working very hard on developing molecules (ultimately a drug) that will correct the abnormal structure of apoE4 and, thus, prevent it from undergoing cleavage that generates the toxic fragments. This work is being done at the biotech company E-Scape Bio that we created. The work is progressing nicely, but a drug remains sometime in the future. As we also discussed, Alzheimer’s disease is a complex disorder, and ultimately, we may need more than one drug to prevent and possibly reverse the disease process.

My personal goal is to understand all the ways that apoE4 injures nerve cells and to prevent those impairments. Thus, despite being involved in the success of the company, I am continuing my research on apoE4 at the Gladstone Institutes. I have become more and more convinced that Alzheimer’s disease is at least in part a metabolic disorder, resulting from dysfunctional mitochondria caused by apoE4. My most recent research focuses on developing a molecule that prevents the apoE4 fragments from interacting with mitochondria and disrupting energy production. We have known for some time that Alzheimer’s disease patients have reduced brain metabolism and a decreased ability to use glucose (i.e., impair energy metabolism). Only a very few studies have tried to understand how and why this occurs. I believe that my research might explain how this occurs and how we might block these detrimental effects. Can we prevent the apoE4 fragments from poisoning energy production in mitochondria? Can we find a molecule that protects the mitochondria? That is the goal.

While I remain optimistic that we will develop a structure corrector working with E-Scape Bio, it is wise, in my opinion, to continue to cover all our bases to attack this terrible disease. That is my commitment to you! I will continue to keep the community informed.

Best regards,
Bob

[Stavia]

Thanks Julie. It's all converging huh

[Julie G]

I had the same thought, Stavia. I love that Dr. M is now turning his attention to mitochondria!

[Lucy5]

Thanks so much for the post, Julie. One of the many reasons I support Dr Mahley's research is that I don't feel he tends to get locked into theory bias. I can also see how much this lovely man wants to help our community (how can you not love that?)

Recurring lack of energy and brain fog comes up on these forums regularly. I know some days I feel 20 years younger than I am; others 20 years older. I've always wondered why that is and am aware most people in my life don't experience this. I'm very excited Bob is following the mitochondria angle wherever it leads and am hoping our good friend can raise the funds he needs to continue with this research.

[cdamaden]

Hi Lucy,
I have explored the brain fog issue and have found various things that have helped. I would love to know the root cause of my having brain fog (my pet theory is leaky gut) but in the meantime I've found some things that can affect it:
1. Food sensitivity. I was really lucky in that I was able to figure out that peppers directly cause me brain fog (some peppers are worse than others but haven't done any more analysis than that - cayenne vs. paprika vs. chili powder vs... ). I know that I have some GI issues (likely leaky gut) that I'm actively pursuing and really hope that by healing my gut the food sensitivities will go away. If you haven't tried an elimination diet (I used Dr. Ballantyne's autoimmune protocol), it is a great first step. (Note that I used to buy the big bags of little sweet peppers and each half-a-dozen a day.... )
2. Sleep, optimally 8 hours a day for the brain I was issued. If I'm having brain fog more than one day in a row, I prioritize sleep. That usually works.
3. Fish oil, I take a lot - 2 capsules of NOW brand DHA-500, each one contains 500 mg DHA and 250 mg EPA.
4. Magnesium, 500 mg per day. I'm not sure if the Mg or Fish Oil helped the most since I started them around the same time but either way I got somewhat better after I started them.
5. Hormone imbalance. When I learned that I had low Testosterone, I went on hormone replacement therapy. My brain fog greatly reduced. I've since weaned myself off the Testosterone and the brain fog hasn't come back, but I'm willing to bet that if I resumed it that my thinking would be clearer. Once again, my hopes are that gut restoration may lead to better hormonal system performance.
6. Vitamin B. Through DNA testing, I learned that I have some methylation issues. I'm still trying to find the right combination of B supplementation but I do notice that brain fog can occur associated with anxiety due to improper B levels. (I'm going particularly heavy on the B vitamins to get my Homocysteine lowered.)
7. Stress. Enough said.

Chris

[Lucy5]

Hi Chris,
Thanks so much for sharing what has worked for you. Since we 4/4s probably have more issues with dysfunctional mitochondria, (one reason I'm so encouraged by Dr. Mahley's current research focus), I'm always interested in feedback from others in our small group. I've addressed some of your points (i.e. methylation), and will look into others I haven't. And yeah, enough said when it comes to stress. Soon as I come up with a foolproof way to manage that one, I'll let you know ...and send you a copy of my book

[Lucy5]

For those members still evaluating organizations most deserving of your 2016 contributions towards Alzheimer's research, you may want to take another look at this fundraising appeal from Dr. Bob Mahley at Gladstone (Oct 28th post by Julie). He and his staff are so devoted to finding solutions to the mischief caused by ApoE4, I remain very hopeful that their research will make a difference for our community some day.