Blood Brain Barrier and AD

[antimatter37]

Here is an interesting article just published in Nature Medicine. It follows up on many years of study on the relationship between cognitive decline and the blood brain barrier (BBB) by the same research group at USC.

https://www.nature.com/articles/s41591-018-0297-y

The major result reported here seems to be that many forms of cognitive decline, including AD, may ultimately begin with a breakdown in the BBB. Further, the BBB breakdown occurs independent of amyloid beta (AB) or Tau status. In other words, if I interpret this result correctly, older persons may exhibit the initial stages of cognitive decline owing to degradation of the BBB PRIOR to any observed increase in AB or Tau. This contrasts with some current thinking that attributes increases in AB and/or Tau as the initial cause for breakdown in the BBB (basically the other way around). Patients who has signs of vascular dementia were excluded from this study.
The authors attribute the BBB degradation to loss of function in the pericytes, which are cells that help maintain the integrity of the BBB in the capillaries of the brain.

If this result is correct, does that mean that after the BBB begins to degrade owing to age or other means, the development of dementia may then follow different "tracks", one of which may be AD with AB and Tau pathologies? Does the specific dementia track that ultimately develops depend on the individual genetics of the person? For example, BBB degradation in ApoE4 carriers may rapidly evolve into the increasing AB and Tau pathologies that are very common in our group.

[mike]

Here is an interesting article just published in Nature Medicine. It follows up on many years of study on the relationship between cognitive decline and the blood brain barrier (BBB) by the same research group at USC.

https://www.nature.com/articles/s41591-018-0297-y

The major result reported here seems to be that many forms of cognitive decline, including AD, may ultimately begin with a breakdown in the BBB. Further, the BBB breakdown occurs independent of amyloid beta (AB) or Tau status. In other words, if I interpret this result correctly, older persons may exhibit the initial stages of cognitive decline owing to degradation of the BBB PRIOR to any observed increase in AB or Tau. This contrasts with some current thinking that attributes increases in AB and/or Tau as the initial cause for breakdown in the BBB (basically the other way around). Patients who has signs of vascular dementia were excluded from this study.
The authors attribute the BBB degradation to loss of function in the pericytes, which are cells that help maintain the integrity of the BBB in the capillaries of the brain.

If this result is correct, does that mean that after the BBB begins to degrade owing to age or other means, the development of dementia may then follow different "tracks", one of which may be AD with AB and Tau pathologies? Does the specific dementia track that ultimately develops depend on the individual genetics of the person? For example, BBB degradation in ApoE4 carriers may rapidly evolve into the increasing AB and Tau pathologies that are very common in our group.

it is now looking like the AB may actually be a defense against leaky BBB

[sarahb12]

So what countermeasures can we do to preserve the BBB? I have just assumed everything for vascular system is good. Anything else?

[antimatter37]

Here is a more general review article covering more of the relationship between the BBB and Alzheimer's. I think is is available for free as well. The title is "Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders".

https://www.ncbi.nlm.nih.gov/pubmed/29377008

As far as supplements go, here is an article listing several that may have some positive effect. The list includes many supplements that folks in our group are already very aware of such as curcumin, resveratrol, Omega 3's, magnesium, and others.

As with Alzheimer's disease itself, breakdown of the blood brain barrier seems to have age as its number one risk factor. Diet and lifestyle changes that are strongly promoted in articles and books to slow down the progression of AD seem to be similarly related to slowing age related BBB degradation. Go figure.

What interests me the most about this line of BBB research is that if indeed loss of BBB function is is a primary initial driver for the cascade of inflammation, AB and Tau buildup, and overall loss of neuron and synapse functionality, it may help explain the ongoing failures of clinical trials that target AB buildup but not the underlying cause of that buildup in the first place. Once the BBB begins to be compromised owing to age and other factors, APOE4 types like us are struck with the most damaging bodily response and over time leading to the ultimate failure of our brain.

[antimatter37]

Here is the article on supplements!
http://www.drnoelthomas.com/blog/2018/1 ... in-barrier

[antimatter37]

A new article has appeared in the well-known journal Neuron, from researchers at the Galdstone Institute in the Bay area.

"Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model"
https://reader.elsevier.com/reader/sd/p ... 2FDD51E08A

Here, the authors show how, beginning with a breach in the blood-brain barrier (BBB), fibrinogen in the blood enters the brain and results in pathogenic microglia activation. This ultimately leads to loss of synapse function, and memory impairment in mice and in humans. Further, the authors state:

"Our study identifies 3D volume imaging of fibrinogen as a sensitive detector of vascular abnormalities in AD. The highly focal fibrinogen deposition pattern we observed in cleared mouse and human brain supports the emerging recognition that cere-brovascular damage, microbleeds, and BBB disruption are key features of AD."

Here is where a more general synopsis of the article can be read:

https://www.genengnews.com/news/fibrino ... lzheimers/

It seems to me that an increasing number of proteins, viruses, bacteria, or other "bad actors" are being associated with AD. In all cases, they seem to need to cross an impaired blood brain barrier as an initial step in the degenerative process.

[aphorist]

I have some notes on this pericyte/BBB issue, as I have read a few of Zlokovic's papers. In the interim, I'll just drop this link:

Sulforaphane inhibits BBB inflammation of pericytes and RAGE/AGE activity.

https://www.ncbi.nlm.nih.gov/pubmed/25241332

[NewRon]

So would this report support the theory of Prof. Gonzalez-Lima, as discussed on Attia's podcast and commented on here, recently?

https://peterattiamd.com/franciscogonzalezlima/

viewtopic.php?f=4&t=5776&p=63729&hilit=attia#p63729

http://www.prostaphane.com/prostaphane/ ... phane.html

[antimatter37]

I think the two approaches are different (I am a non-expert). The blood-brain barrier (BBB) is primarily constructed of cells that surround the tiny capillaries throughout the brain, and are thus external to the capillaries themselves. Degradation in these BBB cells, through age or other means, results in foreign agents such as viruses, bacteria, proteins in the blood, and other entities that normally do not have access to the brain cellular areas gaining access. These foreign agents begin to create immune system havoc, inflammation, AB buildup, etc., ultimately resulting in loss of brain function and brain cell death.

The Lima hypothesis seems to be more concerned with capillary internal health, i.e., narrowing of these capillaries resulting in reduced blood flow to the brain. This reduced blood flow results in lower brain cell metabolism, and ultimate loss of brain cell function.

It could be that both of these mechanisms, and possibly several others, are actually in play as AD develops. As age is still the largest risk factor for AD, one need only to think of the many age related issues we face and how many of these play some role in AD. The BBB aspect is of interest to me right now as there have been so many publications recently that implicate some sort of pathogen (fibrogenin, dental plaque bacteria, HSV virus, retroviruses, and others) in the progression of AD. One thing they all have in common is the need to cross the BBB, which does not seem to happen much to young persons but as we age and the BBB deteriorates they may become a much greater factor.

[NewRon]

Ok, interesting, isn't it?

Anyway, keep taking the (Prostophane) tablets