Blood brain barrier and Alzheimer's

There is a fascinating article in this month’s Scientific American. There is no point in linking to it since it is behind a paywall. But I will try to summarize the salient features. It describes a series of experiments carried out on mice (and so the tentative conclusions may be of more interest to the mice among you)

  1. The first experiments demonstrated that extreme stress can cause holes to develop in the blood brain barrier (BBB). They were motivated by evidence in Gulf War I veterans.

  2. The next series showed that blood in the brain led to Alzheimer-like symproms (which I will call, for this post only, ALS).

  3. The next series examined each component of the blood and showed that the one that led to ALS was albumin.

  4. The next series showed that the albumin bonded to a kind of neuron called an astrocyte, eventually resulting in brain inflammation and ALS.

  5. The next experiment was to breed some GMO mice whose astrocytes lacked the receptor that bonded to albumin. These mice did not develop ALS in response to albumin. The article does not mention if blocking those receptors had any other significant effects.

  6. It turned out there was an already known drug (called IPW) that specifically blocks that receptor on the astrocyte. The next experiments consisted in treating* the mice with IPW. Not only did this block the ALS in mice, it reversed, to some extent although not completely, the ALS in mice that had already shown signs of dementia.

And the article essentially stopped there. Although it mentioned that the two authors plus the man who told them about the IPW, had formed a company.

*Treated how? Doesn’t say. Do you have to open the brain case and spray it in? Or inject it and assume it can get to the brain through the holes in the BBB? Or swallow it? Side effects? It was originally an anti-cancer drug, so even serious side effects might be acceptable.

Article form June 2020 on the same drug and potential impact on Alzheimers.

" TO DEVELOP A DRUG TO TREAT HUMANS, Kaufer, Friedman, and Hart have since started a company, Mend Neuroscience. Though shelter-in-place has thrown a wrench in their timeline, Kaufer hopes the company can start clinical trials in a few years."

“She tries to respond to every email, but she knows that she’s years away from clinical trials, let alone FDA approval and a market-ready therapy.”

Basically lots of articles in Scientific American summarize scientific articles published in scientific/scholarly journals. Hari, perhaps you could check the bibliography and find some of these which may be publicly available. Here is one possibility:

Unlike most Sci-Am articles, there are no references. The authors are Daniela Kaufer and Alon Friedman so you could search for their papers.

If their hypothesis is correct, that would explain why drugs that clear beta-amyloid have been totally useless for Alzheimer’s.

Did the article specify if the drug was IPW-5371? I was curious enough to try to track it down. It’s turning into quite the rabbit hole. For instance:

Given the probable involvement of TGF-β in the progression of COVID-19, a preclinical, anti-TGFβ receptor 1 product, IPW5371 (Innovation Pathways, Palo Alto, CA) may also be a promising candidate to treat COVID-19-induced lung fibrosis, as it has previously been shown to reduce fibrosis and improve survival in a mouse model of radiation exposure

Source. My bold.

There will be people on these boards who are far better qualified to explain what’s happening here than I am; but you do see spurts of interest in the way a new drug impacts biological pathways, and then that fans out to preclinical testing in a range of disease conditions - sometimes because there’s an obvious lead, sometimes because there’s a hot topic of interest (COVID would qualify). It can feel a bit like a solution looking for a problem - not that that is necessarily a bad thing.

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You may have it. Here is the relevant sentence from the article:

Barry Hart, a medicinal chemist at Innovation Pathways, a start-up drug company in Palo Alto, Calif., had designed an anticancer drug that specifically blocked the activity of the TGFβ receptor. Hart contacted us and suggested that we try the drug, called IPW, on our mice.

The TGF-beta receptor in the astrocyte was the receptor that bonded to the albumin. Note the company Innovation Pathways. As a subscriber, I was able to download the article, but of course I cannot post it.

My daughter was able to get the link:

But she used to work for Nature which is affiliated with Sci-Am so her computer may automatically link. I am interested to know if this works for others.

Yep, the link works. Interesting read.

I’m pretty sure the (early!) investigative drug must be IPW-5371.

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