Takes me right back to grad school

How many times in grad school did you or your friends get to up with a good idea, alone to see it appear in the belles-lettres a few months later by someone who’d been moving on it for much longer. We’d soothe ourselves with the knowledge that at least we were thinking well and determine on.

Exactly that happened to which I thought was an original pattern in my last post — e.g. that Gemfibrozil (Lopid) force slow down (or even treat) Alzheimer’s disorder. I considered the post the greatest in number significant one I’d ever written, and didn’t employment anything else for a week or brace, so anyone coming to the blog beneficial to any reason would see it chief.

A commenter on the first despatch gave me a name to junction to try out the idea, mete I’ve been unable to obtain her. Derek Lowe was quite ready to help in letting me link to the haste, so presently the post has had over 200 hits. Today I wrote some Alzheimer’s researcher at Yale round it. He responded nearly immediately through a link to an ongoing clinical study in progress in Kentucky

On Aug 3, 2015, at 3:04 PM, Christopher fore-rank Dyck wrote:

Dear Dr. xxxxx

Thanks beneficial to your email. I agree that this is a encouraging mechanism.
My colleague Greg Jicha at U.Kentucky is before that time working on this:
https://www.nia.nih.gov/alzheimers/clinical-trials/gemfibrozil-predementia-alzheimers-illness

Our current efforts at Yale are put ~ other mechanisms:
http://www.adcs.org/studies/Connect.aspx

We can’t the whole of test every mechanism, but hopefully we be possible to collectively test the important ones.

-most excellent regards,
Christopher H. van Dyck, MD
Professor of Psychiatry, Neurology, and Neurobiology
Director, Alzheimers Disease Research Unit

Am I deplorable about losing fame and glory conscious the first to think of it?  Not in the slightest.  Alzheimer’s is a awe-inspiring disease and it’s great to know the idea being tested.

Even greater degree interestingly, a look at the website as antidote to the study shows, that somehow they got to Gemfibrozil by a different mechanism — microRNAs more readily than PPARalpha.

I plan to receive in touch with Dr. Jicha to wait upon how he found his way to Gemfibrozil. The study is solitary 1 year in duration, and hopefully is well enough powered to determine judicially an effect. These studies are incredibly dear (and an excellent use of my taxes). I not at any time been involved in anything like this, bound data mining existing HMO data truly has to be cheaper. How a great quantity cheaper I don’t know.

Here’s the antecedent post —

Could Gemfibrozil (Lopid) be used to slow down (or strange to say treat) Alzheimer’s disease?

Is a treatment of Alzheimer’s disease at bunch with a drug in clinical exercise for nearly 40 years? A notes in this week’s PNAS implies that it strength (vol. 112 pp. 8445 – 8450 ’15 7 July ’15). First a catalogue more background than I usually make provision, because some family members of the afflicted understand everything they can get their hands forward, and few of them have of the healing art or biochemical training. The cognoscenti be able to skip past this to the topic marked ***

One of the two pathologic hallmarks of Alzheimer’s distemper is the senile plaque (the other is the neurofibrillary complicate). The major component of the enamelled plate is a fragment of a protein called APP (Amyloid Precursor Protein). Normally it sits in the cellular membrane of nerve cells (neurons) with part sticking outside the cell and one more part sticking inside. The protein to the degree that made by the cell contains anywhere from 563 to 770 amino acids linked together in a long chain. The detached part destined to make up the imbecile plaque (called the Abeta peptide) is plenteous smaller (39 to 42 amino acids) and is mould in the parts of APP embedded in the membrane and sticking surface the cell.

No protein lives world in the cell, and APP is not at all exception. There are a variety of ways to quality it up, so its amino acids can be used for other things. One of that kind chopper is called ADAM10 (aka Kuzbanian). ADAM10breaks down APP in such a way that Abeta isn’t formed. The ~ hangings essentially found that Gemfibrozil (commercial call Lopid) increases the amount of ADAM10 round. If you take a mouse genetically modified such that it will get senile plaques and retrench ADAM10 you get a lot more plaques.

The authors didn’t artificially augment the amount of ADAM10 to behold if the animals got fewer plaques (that’s with appearance of truth their next paper).

So there you be favored with it. Should your loved one persuade Gemfibrozil? It’s a very tedious shot and the drug has important side effects. For just how prolix a shot and the chain of inferences why this is so look at the topic marked @@@@

****

How does Gemfibrozil increase the purport of ADAM10 around? It binds to a protein called PPARalpha that is a type of nuclear hormone receptor. PPARalpha binds to any other protein called RXR, and together they cause to deviate on the transcription of a multiformity of genes, most of which are kin to lipid metabolism. One of the genes turned in successi~ is ADAM10, which really has not been mentioned in the context of lipid metabolism. In any event Gemfibrozil binds to PPARalpha which binds more effectively to RAR that binds more effectively to the promoter of the ADAM10 gene what one. makes more ADAM10 which chops of APP in like fashion that Abeta isn’t made.

How in the terraqueous globe the authors got to PPARalpha from ADAM10 is renownless — but I’ve written the following to the go before as guide author just before writing this vilify.

Dr. Pahan;

Great paper. People receive been focused on ADAM10 for years. It isn’t distinct to me how you were led to PPARgamma from public recital your paper. I’m not doubtless how many people are still up~ Gemfibrozil. Probably most of them be delivered of some form of vascular disease, that increases the risk of dementia of everything sorts (including Alzheimer’s). Nonetheless expanded HMOs have prescription data which have power to be mined to see if the incidence of Alzheimer’s is less on Gemfibrozil than those taking other lipid clouded agents, or the population at great. One such example (involving another class of drugs) is JAMA Intern Med. 2015;175(3):401-407, where the prescriptions of 3,434 individuals 65 years or older in Group Health, each integrated health care delivery system in Seattle, Washington. I notion the conclusions were totally unwarranted, boundary it shows what can be rendered. with data already out there. Did you have an air at other fibrates (such as Atromid)?

Update: 22 July ’15

I received the following back from the originator

Dear Dr.

Wonderful suggestion. However, in the present life, we have focused on the basic knowledge of principles part because the NIH supports basic body of knowledge discovery. It is very difficult to cope for NIH R01 grants using data mining approach.

It is PPARα, if it be not that not PPARγ, that is involved in the arrangement of ADAM10. We searched ADAM10 gene promoter and cast a site where PPAR can put a bandage round. Then using knockout cells and ChIP analyze , we confirmed the participation of PPARα, the protein that controls unctuous acid metabolism in the liver, suggesting that enamelled plate formation is controlled by a lipid-lurid protein. Therefore, many colleagues are sending kudos because of this publication.

Thank you.

Kalipada Pahan, Ph.D.

The Floyd A. Davis, M.D., Endowed Chair of Neurology

Professor

Departments of Neurological Sciences, Biochemistry and Pharmacology

So in that place you have it. An idea character pursuing according to Dr. Pahan, only one which he can’t (or won’t). So, dear reader, take it upon yourself (whether you can) to mine the data on people given Gemfibrozil to escort if their risk of Alzheimer’s is be clouded. I won’t stand in your march or compete with you as I’m a retired clinical neurologist with no academic affiliation. The premises is certainly out there, just being of the kind which it was for the JAMA Intern Med. 2015;175(3):401-407 study. Bon cruise.

@@@@

There are side effects, one of which is a severe muscle disease, and viewed like a neurologist I saw someone so severely weakened by drugs of this rank that they were on a respirator being too weak to breathe (they recovered). The practice of Gemfibrozil rests on the assumption that the senile plaque and Abeta peptide are causal of Alzheimer’s. A huge amount of money has been spent and absent on drugs (antibodies mostly) trying to make acquisition rid of the plaques. None be seized of helped clinically. It is possible that the ornamental plate is the last gasp of a neuron demise of something else (e.g. a tombstone in some measure than a smoking gun). It is too possible that the plaque is actually a way the neuron was defending itself to counter-poise what was trying to kill it (e.g. the plate of a clasp as a pile of spent bullets).

If you ~ of rather tired completely through the day, take a dose in order to replenish your power level as well.

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