I understand that persons with AIDS eventually are found with pathologies in the brain that could not have developed in the brain because of the inability of the organism to pass the BBB. For instance an avian type of TB has been found upon brain autopsy of people who died from AIDS.

Titre du document / Document title
The role of blood-brain barrier in neurodegenerative diseases
Auteur(s) / Author(s)
DELI Maria A. (1) ; Di Liegro Italia (Editeur scientifique) ; Savettieri Giovanni (Editeur scientifique) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Laboratory of Molecular Neurobiology, Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62, 6726 Szeged, HONGRIE

Résumé / Abstract
The proper functioning of blood-brain barrier (BBB) is indispensable for the proper functioning of the central nervous system (CNS). Besides maintaining the ionic homeostasis necessary for neuronal activity, BBB provides nutrients to the cells of nervous system, and protects them from xenobiotics. It has long been known that opening of the BBB and the penetration of serum components to brain parenchyma damages the CNS in several pathological conditions. It has also become clear, that even subtle functional changes without morphological alterations can lead to severe and lasting neurological dysfunction. This review summarizes the changes found in BBB morphology and function in selected neurodegenerative diseases: Alzheimer's disease, prion diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and human immunodeficiency virus 1 (HIV-1) associated neurological disorders. In these pathologies cerebral endothelial cells are often directly damaged by pathological factors. Since the maintenance of the BBB phenotype depends on the crosstalk between cerebral endothelium and neighbouring astrocytes and other perivascular cells, an indirect damage can derive from the insufficient signalling from dysfunctional glia and pericytes. In both cases the consequence is damage to BBB functions leading to disturbed brain homeostasis and neuronal loss. Moreover, injured brain endothelial cells can release neurotoxic factors. As a conclusion BBB can be seriously affected in neurodegenerative disease, while in turn BBB damage and dysfunction can contribute to the progress of neurodegenerative diseases. The dysruption of this vicious circle by protecting brain endothelial cells could be clinically relevant.
Source / Source
Molecular bases of neurodegeneration
2005, pp. 137-161, [Note(s) : 230] (119 ref.) ISBN 81-7736-261-5 ; Illustration : Figure ;
Langue / Language
Anglais

Editeur / Publisher
Research signpost, Trivandrum, INDE (2005) (Monographie)

Mots-clés anglais / English Keywords
Spinal cord disease ; Genetic disease ; Nervous system diseases ; Parkinson disease ; Prion ; Alzheimer disease ; Morphology ; Review ; Degenerative disease ; Dysfunction ; Parenchyma ; Encephalon ; Nervous system ; Nutrient ; Homeostasis ; Central nervous system ; Blood brain barrier ;
Mots-clés français / French Keywords
Moelle épinière pathologie ; Maladie héréditaire ; Système nerveux pathologie ; Parkinson maladie ; Prion ; Démence Alzheimer ; Morphologie ; Article synthèse ; Maladie dégénérative ; Trouble fonctionnel ; Parenchyme ; Encéphale ; Système nerveux ; Nutriment ; Homéostasie ; Système nerveux central ; Barrière hématoencéphalique ;
Mots-clés espagnols / Spanish Keywords
Médula espinal patología ; Enfermedad hereditaria ; Sistema nervioso patología ; Parkinson enfermedad ; Prion ; Demencia Alzheimer ; Morfología ; Artículo síntesis ; Enfermedad degenerativa ; Trastorno funcional ; Parénquima ; Encéfalo ; Sistema nervioso ; Nutriente ; Homeostasis ; Sistema nervioso central ; Barrera hematoencefálica ;
Localisation / Location
INIST-CNRS, Cote INIST : L 30607, 35400015365019.0070


Copyright 2007 INIST-CNRS. All rights reserved

Toute reproduction ou diffusion même partielle, par quelque procédé ou sur tout support que ce soit, ne pourra être faite sans l'accord préalable écrit de l'INIST-CNRS.
No part of these records may be reproduced of distributed, in any form or by any means, without the prior written permission of INIST-CNRS.

Nº notice refdoc (ud4) : 18315992

Reread the abstract in post number 20 and then the one below and you may have another piece of the puzzle. The glia cluster around the BBB/capillaries not to repel invaders but to put a metabolic finger in the dike.

I am going to try to put some of this together in a second post to get away from the clutter, but we may have something here...


1: Glia. 2003 Apr 1;42(1):46-58.

Protective effect of glial cells against lipopolysaccharide-mediated blood-brain
barrier injury.

Descamps L, Coisne C, Dehouck B, Cecchelli R, Torpier G.

Sanofi-Synthelabo Recherche, Montpellier, France.

Numerous infections of the central nervous system are characterized by altered
blood-brain barrier (BBB) functions leading to brain damage. To study the
mechanisms that cause BBB disruption in these pathologies, we used an in vitro
BBB model consisting of a coculture of brain capillary endothelial cells and
glial cells. When these endothelial cells were submitted alone to
lipopolysaccharide (LPS), added in the luminal compartment, a huge increase in
the paracellular permeability of the monolayer was observed. As glial cells
surrounding the brain capillaries are of prime importance in specifying at least
some cellular properties, we investigated whether glial cells would be able to
modulate this endothelial cell response to LPS. When endothelial cells were
incubated with LPS added luminally, in the presence of glial cells, LPS
surprisingly had no effect on the endothelial cell monolayer permeability,
suggesting a protective effect of glial cells on the LPS-mediated injury. As in
our experiments, the endotoxin does not interact with the glial cell population.
This protective effect suggests a close communication between cerebral
endothelial cells and brain parenchymal cells. In our coculture model, the glial
cell population is a mixture of astrocytes, oligodendrocytes, and microglial
cells. Further experiments performed with purified astrocytes showed that
microglial cells or oligodendrocytes, or both, are essential for the complete
protection of the endothelial cell monolayer integrity. All these results are
direct evidence for a modulatory effect of glial cells on brain capillary
endothelial cell response in the pathogenesis of endotoxemia. Copyright 2003
Wiley-Liss, Inc.

PMID: 12594736 [PubMed - indexed for MEDLINE]

See if this holds up-

1- Prenatal exposure to bacterial toxin LPS sets up an alterred immune response in the brain's defenders (the glia) which is a sort of hypersensitivity to any hint of LPS and an overly exuberant response when actual contact occurs. Researchers P.M. Carvey and Bin Liu have covered this pretty well.

2- So, infection as far away as your toe sends signals that cause the glia to rush to the dike. Usually, it is a false alarm since the infections are minor or far away. But even this vigilance takes a toll.

3- One day you come down with a more serious infection that sends a real load of LPS against the dike - already weakened and leaky from number 2 above plus stress and god only knows what else. The leaks multiply and LPS tself enters the brain. Like poor Stefi's soggy carpet in her flooded basement, it is a real mess and toxic too.

4- The second part of prenatal effect now comes into play as the glia abandon their shovels at the dike and draw swords against their assumed foe. Only the foe is either sending toxin from a distance or is mixed in with the townspeople (the neurons) and the BBB isn't getting any better. So you end up with a lot of collateral damage, a leaky dike, and so on.


That would explain a lot, such as why so many of us remember being sick or unusually stressed just before our symptoms.

Rick,
Good thinking, but does it need to be prenatal exposure initially.
Infection/ LPS exposure can occur probably, at any time in your lifetime,and
can damage the BBB, which is growing more permeable with age in any case. The weakened BBB reaches the point where dopamine can leak out, toxins and carbidopa can leak in, and you have PD. Remember the entcephylitus (spelling?) outbreak, where all who caught it, subsequently got PD. There was presumably no prenatal exposure there.
This track may lead us to the treatment we are looking for, which could close up/ repair the BBB, and remove the PD symptoms. For example see
http://www.sciencedirect.com/science...1e96f367e6c5f9

Where the title is
"Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages "
So there is our first candidate in the fight back. It also says, that the
pentosan polysulfate is a polyanionic polysaccharide and
could reduce the deleterious effects of LPS on BBB permeability
Ron

Neurochemistry International
Volume 50, Issue 1, January 2007, Pages 219-228

Abstract
Peripheral inflammation can aggravate local brain inflammation and neuronal death. The blood–brain barrier (BBB) is a key player in the event. On a relevant in vitro model of primary rat brain endothelial cells co-cultured with primary rat astroglia cells lipopolysaccharide (LPS)-induced changes in several BBB functions have been investigated. LPS-treatment resulted in a dose- and time-dependent decrease in the integrity of endothelial monolayers: transendothelial electrical resistance dropped, while flux of permeability markers fluorescein and albumin significantly increased. Immunostaining for junctional proteins ZO-1, claudin-5 and β-catenin was significantly weaker in LPS-treated endothelial cells than in control monolayers. LPS also reduced the intensity and changed the pattern of ZO-1 immunostaining in freshly isolated rat brain microvessels. The activity of P-glycoprotein, an important efflux pump at the BBB, was also inhibited by LPS. At the same time production of reactive oxygen species and nitric oxide was increased in brain endothelial cells treated with LPS. Pentosan polysulfate, a polyanionic polysaccharide could reduce the deleterious effects of LPS on BBB permeability, and P-glycoprotein activity. LPS-stimulated increase in the production of reactive oxygen species and nitric oxide was also decreased by pentosan treatment. The protective effect of pentosan for brain endothelium can be of therapeutical significance in bacterial infections affecting the BBB.

Keywords: Blood–brain barrier; Rat brain endothelial cell; Lipopolysaccharide; Pentosan polysulfate; Permeability; P-glycoprotein; Nitric oxide

The problem is that there has to be a factor that keeps us as a minority. If it is JUST that LPS weakens the BBB then there should be many more of us. Everyone of us grows up with LPS so it isn't that some encounter it and some don't.

Genetics alone won't explain it or we would see a stronger hereditary profile.

Prenatal LPS at times of vulnerability would satisfy the statistical problem since only a few would have mothers who had an infection on the day the particular part of the brain was forming.

The kicker is the over reaction of the microglia once the BBB fails. This has been intentionally demonstrated in rats. Two other things- the substantia nigra has one of the highest populations of microglia in the brain. And micoglial activity increases with age even in normal folk.

Another thought just occurred to me. It could be that whatever the microglia are doing to hold the dike could be the point of failure. If it is a repair or reinforcement function and it's failure is the last blow, that might offer a therapeutic avenue.

By the way, I was looking at a Word doc that I had written up on the LPS angle when I first ran across it. The author was listed in the header as "Ron Hutton" ! I had typed it up on your machine during our visit.

Rick,
I believe the reason we are in a minority is that not everyone was born with an identical BBB permeability, and others will damage their BBB in later life. I tried to illustrate this with my imagined BBB permeabilities. Say a healthy range is 100 to 120. Some of these people will increase their permeability through stress, environmental insult, blow to the head, etc. An infection or virus may also cause an increase. Some may be born with a higher figure than normal.(Just as some are born with defective hearts etc.)

When a person gets to say, 160, PD symptoms start. Many will be getting to danger levels when they reach old age, since permeability increases with age.
It is unlikely that exposure to LPS is the only cause, since it
is a bacteria that not everyone wiil be subject to it at high levels. It is said to be " LPS is a major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria,"
LPS is only one kind of substance which can damage the integrity of the BBB, there are others, eg MTPT.
Over 50% of us have helicobacter infection, yet 50% don't have PD, only the ones who have a defective BBB.
If you have luck on your side, you will be born with a healthy BBB. If you take care of it, it will last you into old age. Avoid infections, pesticides, viruses, physical head trauma etc, as far as possible. Take powerful antioxidants like curcumin, alpha lipoic acid etc which have been shown to reduce permeability and protect the BBB. Just like don't damage your lungs and heart by smoking!
I believe these are the reasons why only a minority get PD, and we all age together, but those with higher permeability values, for whatever reason, will develop PD. There is an inexorable rise in permeability with age,
explaining as we have said before, why it is (mainly) an old person's disease.
Thanks for reminding me of your stay in Merry England, we had some real good times.
Ron

I took me a while to try and get things straightened out. I’ve discussed the issue on a dutch chemistry forum but I just can’t seem to find someone who really knows how the carrier system of the BBB works.
What I was trying to do is to connect some theories on the origin of Parkinson’s disease. There are quite a few theories that thrive an overall explanation. There is the methylation theory that I mentioned and closely related the oxidative stress theory and the heavy metals theory. Further I ‘d like to mention mitochodrial respiratory failure as a cause. Some even say PD is a mitochondrial disease.

What I want remark is that your BBB theory is plausible but what I think we need is an insight in the mechanisms of how the BBB is destructed. Why do heavy metals or carbon dioxide do such a thing..

An example of heavy metal intoxication is the case of mercury intoxication When mercury arrives in the liver, that organ does what it knows to do to detoxify a poison, it is methylated, that is a methyl group (-CH3) is attached to it. Unfortunately, in the case of mercury, this makes it more toxic by a factor of 100.

MeHg in blood plasma can combine with cysteine, forming a compound that is structurally similar to the amino acid methionine.
This MeHg-cysteine compound is actively transported into the endothelial cells in the BBB, on the methionine carrier.
A high level of reduced glutathione is maintained in the endothelial cells, and the MeHg switches from a cystein carrier to a glutathione carrier.
MeHg-glutathione is actively transported out of the endothelial cells and into the brain. In the brain, the hydrolysis of MeHg-glutathione generates MeHg-cysteine. ( http://www.mercuryexposure.org/index.php?page_id=32 )

But I really don't want to discourage you. In fact I strongly believe in patients cooperating in research. I 'd like to recommend our website www.parkinsonhuis.nl where we try to find correlations in parkinson symptoms. So, if you please, fill in the questionnaire. Up to now more than 800 patients did, and soon we expect to publish some remarkable results.

Joop,
Thanks very much (Dank U well!) for your reply. Firstly, as I explained, I only speak a limited amount of Dutch, (Ik kan alleen een beetje Nederlands spreken). Your website is in Dutch and it would take me a long time to fill in the form.
I agree there are a number of theories for the cause of PD, and the oxidation theory pioneered by Professor Jenner is also very feasible. As an ex researcher, we used to judge a theory by the number of facts that it can explain. See the list of questions and answers in my earlier post in this thread. I can't see the methylation idea answers many of the questions I have tried to answer by the BBB theory.
Mercury is methylated, in the body and in nature, but I can't see a connection with PD. There was considerable mercury pollution in Tokyo Bay, and this resulted in high methyl mercury levels. However, the locals suffered from joint pains, not PD. The illness was called Itai Itai disease, meaning "It hurts, It hurts". There was not a hotspot of PD.
There is more and more evidence and support for the BBB theory.
Thanks again for your input.
Ron

See PMID: 17503739
http://www.ncbi.nlm.nih.gov/sites/en...indexed=google

Cell Transplant. 2007;16(3):285-99.Links
Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy.Desai BS, Monahan AJ, Carvey PM, Hendey B.
Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA. Brinda_Desai@rush.edu

The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.

PMID: 17503739 [PubMed - indexed for MEDLINE]

Ron,

Most of the website is in dutch, but on the main page there is a section in English, which links to the questionnaire. To make it easier here is a direct link.
http://www.parkinsonhuis.nl/parkinso...estionaire.htm

I agree that the theory that explains the most is the better theory. But to me there is only one reality and in the end all plausible theories must be united.

The example of mercury intoxication was meant to illustrate how methylated heavy metals can injure the brain and maybe the blood-brain barrier.

Please look at this article. It has an impressive list of references.

http://qjmed.oxfordjournals.org/cgi/.../full/98/3/215