New Research on Blood Brain Barrier and APOE4

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deborahk
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New Research on Blood Brain Barrier and APOE4

Postby deborahk » Wed Jun 10, 2020 10:28 pm

Researchers are making headway in explaining why people who carry the ApoE4 gene, the largest genetic risk factor for Alzheimer’s, are more likely to suffer from damaged blood-brain barriers.

It was never clear to researchers whether the ApoE4 gene was responsible for the early malfunction of the blood-brain barrier, a protective barrier shielding the brain from toxins or pathogens, or whether it worked together with the proteins beta-amyloid and tau.

Here's our recent article:

https://www.beingpatient.com/apoe4-damages-protective-barrier-of-the-brain/

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Re: New Research on Blood Brain Barrier and APOE4

Postby SusanJ » Thu Jun 11, 2020 9:07 am

“It turned out that the pericytes from the ApoE4 cells drastically increased their expression level of ApoE,” said Li-Huei Tsai, Picower Professor of Neuroscience and Director of the Picower Institute For Learning and Memory at MIT.

The scientists then identified a pathway that elevated ApoE expression, triggering more beta-amyloid to accumulate.

“The reason why knowing the pathway is important is because we already have FDA-approved small molecules that can inhibit this pathway,” Tsai said.

One of the FDA-approved drugs that the team tested is currently used to prevent organs from shrinking after transplants. And Tsai pointed to an intriguing finding from past studies: “There are known publications following those individuals who received organ transplant under medication with this drug,” Tsai said. “These people turned out to have a much reduced incident of developing dementia.”


Most hopeful thing I've read in a while.

deborahk wrote:Meanwhile, the researchers found that the drug reduced the levels of ApoE proteins and the buildup of beta-amyloid after administering it in mice and blood-brain barrier models.


Do you know what drug they were looking at? The paper is behind a paywall...

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Re: New Research on Blood Brain Barrier and APOE4

Postby antimatter37 » Fri Jun 12, 2020 9:50 am

Took a look at the article

Published: 29 April 2020
APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline
Axel Montagne, Daniel A. Nation, […]Berislav V. Zlokovic
Nature volume 581, pages71–76(2020)

There is no mention that I can find regarding these small molecules. I will check again with a slower read-through. The basic conclusion that these authors reach is that APOE4 types suffer greater BBB breakdown over time than their APOE3 cohorts, owing primarily to the degradation in pericyte function surrounding the brain blood vessels. This BBB breakdown leads to cognitive impairment in the APOE4 individuals but is NOT correlated with increased levels of AB or TAU in the APOE4 brains.

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Re: New Research on Blood Brain Barrier and APOE4

Postby SusanJ » Sat Jun 13, 2020 7:55 am

antimatter37 wrote:The basic conclusion that these authors reach is that APOE4 types suffer greater BBB breakdown over time than their APOE3 cohorts, owing primarily to the degradation in pericyte function surrounding the brain blood vessels. This BBB breakdown leads to cognitive impairment in the APOE4 individuals but is NOT correlated with increased levels of AB or TAU in the APOE4 brains.


I haven't had a chance to dig any further into this, so thanks for taking a look. I just found the correlation of transplant patients to lower dementia rates an interesting one and wondered what immune-suppression pathway that drug was targeting, and what might be that pathway's relationship to the health of pericytes.

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Re: New Research on Blood Brain Barrier and APOE4

Postby antimatter37 » Sat Jun 13, 2020 10:56 am

There are research groups studying the drug rapamycin for potential efficacy in "life extension". If I had to guess, this particular anti-rejection drug could be the one referred to in the first post.

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Re: New Research on Blood Brain Barrier and APOE4

Postby BrianR » Sat Jun 13, 2020 1:40 pm

SusanJ wrote:Do you know what drug they were looking at? The paper is behind a paywall...

I used SciHub to peek behind the paywall. Here are some extracts from the paper. Note their human cell work was apparently in vitro, so we'll have to see how their calcineurin inhibitors do in actual humans. (The inhibitors do seem to help in their mouse model and, anecdotally, in humans.)
Abstract
In Alzheimer’s disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood–brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin–nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin–NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin–NFAT signaling as a therapeutic target in CAA and Alzheimer’s disease.

... [from the body of the paper] ...

Inhibition of calcineurin reduces APOE expression and ameliorates Aβ deposition. To determine whether dysregulation of NFAT–calcineurin signaling in APOE4 pericytes contributes to upregulated APOE expression, we inhibited calcineurin signaling in iMCs using the well-established calcineurin inhibitors cyclosporine A (CsA) (2 μM), FK506 (5 μM) and INCA6 (5 μM) (Extended Data Fig. 7a). After 2 weeks, each of the three inhibitors significantly reduced APOE expression in APOE4/4 iMCs as measured by qRT–PCR (Fig. 5a). Calcineurin inhibition did not significantly reduce constitutively expressed proteins such as PGK1, HPRT and GAPDH, suggesting that APOE downregulation is not due to cellular death or global transcriptional repression (Extended Data Fig. 7b). APOE3/4 heterozygous iMCs also exhibited a significant reduction in APOE mRNA expression when treated with each of the three calcineurin inhibitors (Fig. 5b). Calcineurin inhibition reduced intracellular APOE protein as measured by immunofluorescence in both APOE4/4 homozygous and APOE3/4 heterozygous iMCs (Extended Data Fig. 7c,d). Likewise, CsA significantly reduced the concentration of soluble APOE protein in iMC medium measured by ELISA (Fig. 5c).
...

Discussion
Here, we developed and validated a human in vitro model of the BBB. While the iBBB recapitulates numerous molecular and physiological features of the in vivo BBB there are clear differences that will benefit from future studies incorporating additional physiological aspects of the BBB and improving the fidelity of iPSC-derived vascular cells. This study revealed that NFAT-mediated upregulation of APOE in human pericytes underlies the pathogenic effects of APOE4 in CAA. We pinpoint that APOE and NFAT are dysregulated in human pericytes in the PFC and hippocampus of APOE4 carriers. We establish that chemical inhibition of calcineurin in APOE4 iMCs reduces APOE mRNA and protein and leads to reduced vascular amyloid accumulation. In vivo administration of calcineurin/NFAT inhibitors to APOE4 AD mice also markedly reduced APOEexpression and vascular amyloid. Interestingly, patients chronically administered CsA or FK506 have long been observed to have significantly lower incidence of dementia compared to the general population. Our results provide new insight into these observations and highlight APOE and calcineurin–NFAT-signaling as potential targets in APOE4-mediated CAA and AD.

Some Acronyms:
BBB blood–brain barrier
CAA cerebral amyloid angiopathy [ie, amyloid deposits along cerebral vasculature]
CsA cyclosporine A
NFAT calcineurin–nuclear factor of activated T cells
PFC human prefrontal cortex
iPSC human induced pluripotent stem cells

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SusanJ
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Re: New Research on Blood Brain Barrier and APOE4

Postby SusanJ » Sat Jun 13, 2020 3:42 pm

BrianR wrote:Here are some extracts from the paper.


Thanks! Looks like calcineurin–NFAT-signaling goes on my down-the-rabbit-hole pile. ;)

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Re: New Research on Blood Brain Barrier and APOE4

Postby Newtothis3/4 » Tue Jul 14, 2020 8:32 pm

Rapamycin is the anti-rejection drug that is cited. It can be used as a prophylactic to never develop AD. It also is an anti-aging drug to extend lifespan and keep one from developing cancer, Parkinson’s, etc. The drug is real and it works. In my opinion, Rapa is the greatest drug anyone could take to keep AD from ever developing, regardless of Apoe status.

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Re: New Research on Blood Brain Barrier and APOE4

Postby LaderaJim » Sun Jul 19, 2020 10:07 pm

Here is a link to to the USC research news release regarding APOE4 and the BBB damage that leads to AD.
https://news.usc.edu/169420
I am particularly keen on this topic because I have APOE 4/4 and two cavernomas which are probably subject to the same problem of 'leaky capillaries' (causing my headaches) for which there seems to be no treatment available - LaderaJim

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Re: New Research on Blood Brain Barrier and APOE4

Postby AKA » Mon Jul 20, 2020 8:56 am

LaderaJim wrote:Here is a link to to the USC research news release regarding APOE4 and the BBB damage that leads to AD.
https://news.usc.edu/169420
I am particularly keen on this topic because I have APOE 4/4 and two cavernomas which are probably subject to the same problem of 'leaky capillaries' (causing my headaches) for which there seems to be no treatment available - LaderaJim


Welcome to the Apoe4.info site, LaderaJim!

Thank you for the link to the USC article and contributing to the topic. As a new poster, I'd like to point out a few areas on the site that might be useful and or interesting.

"How-To" Get the most out of the ApoE4.info website
This section offers tips on navigating, responding to posts, following threads, and more.

Primer
The Primer is an introduction to ApoE4, biochemistry, and possible prevention strategies. You may have already read through this section but I like to highlight it as it is chock-full of info.

Looking forward to learning more with you, LaderJim!
Again, a Warm Welcome to You!
Andrea
Apoe4 Intern


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