Blood-Brain Barrier's Role in Alzheimer's Prevention

Blood-Brain Barrier’s Role in Alzheimer’s Prevention

Added as Appendix V in my book "Prevent Alzheimer's, Autism, and Stroke"

Here is a link to my book https://www.amazon.com/Dennis-N-Crouse-Ph-D/e/B01LFW4782?ref=sr_ntt_srch_lnk_1&qid=1587822164&sr=8-1

My wife Laurie Adamson has set up a facebook group Alzheimer's: Late and Early Onset, APOE4 https://www.facebook.com/groups/509038829797535/

The blood-brain barrier (BBB) protects the brain from blood-borne toxic molecules inside the vasculature (e.g. arteries, veins, and capillaries) from entering the space occupied by neurons. In the brain there is an extensive neurovasculature that comprises the BBB. This primarily consists of a capillary bed connected to the choroid plexus that regulates chemical transfer from the blood to the fluids of the brain. These brain fluids include interstitial and cerebrospinal fluids (CSF), the latter being produced by the choroid plexus. The BBB is made of cerebrovascular endothelial cells that are tightly wedged together in the walls of the vasculature and two additional cell types called astrocytes and microglial cells.

Primary factors causing increased BBB permeability to blood-borne toxic molecules are:

·         Aluminum^668-670

·         Traumatic Brain Injury (TBI)^671,672

Aluminum chloride has been shown to increase the permeability of the BBB to lipophilic molecules⁶⁶⁸. Lipophilic molecules are more soluble in fat or hydrocarbon solvents than water. Also both acute and chronic traumatic brain injury has been shown to increase the permeability of the BBB^671,672.

Four factors that are not a cause but are associated with increased BBB permeability: 

·         Alzheimer’s Disease⁶⁷³

·         Vascular Disease – High Blood Pressure and Stroke⁶⁶⁹

·         Ageing⁶⁷⁴

·         Parkinson’s Disease^675,676

Aluminum is a causal factor of both Alzheimer’s and vascular disease.  Aluminum accumulates in the brain with age accounting for why aging is a non-causal factor associated with increased BBB permeability⁶⁷⁴. Traumatic brain injury and increased BBB permeability are associated with parkinsonism^643,675,676. 

There are two ways aluminum disguises its self in order to cross the BBB:

·         Bonding with lipophilic ligands

·         Bonding with carrier proteins that have receptors on the BBB

In the blood lipophilic and non-lipophilic ligands have an affinity for aluminum.  Examples of lipophilic ligands include medium and long chain fatty acids. Aluminum in the serum increases the permeability of the BBB allowing complexes of aluminum with lipophilic ligands, such as fatty acids, to enter the brain. An example of a carrier protein is transferrin that normally carries iron to the brain. Aluminum in the serum competes with iron for transferrin’s two bonding sites.  This allows aluminum, disguised as iron, to enter the brain. These factors allow slow accumulation of aluminum in the brain leading to Alzheimer’s disease.

Aluminum increases the permeability of the BBB by decreasing the expression and production of F-actin, a protein for endothelial cell-to-cell adhesion, and occludin, a plasma-membrane protein located at tight-junctions between endothelium cells, both of which are required for BBB integrity.  Zinc protects the integrity of the BBB in spite of aluminum by increasing the expression in the BBB of both F-actin and occludin. This was demonstrated by dosing simultaneously with both aluminum and zinc⁶⁷⁰. 

The primary factor slowing the accumulation of aluminum in the brain is orthosilicic acid. Orthosilicic acid can cross the BBB and chelate (i.e. complex with) aluminum forming aluminosilicates in both the serum and CSF.  Aluminosilicates are non-lipophilic complexes that do not cross the BBB, even when the BBB’s integrity has been impaired by aluminum. By forming these complexes, orthosilicic acid enhances the elimination of aluminum from the body by both urination and perspiration^36,515.

Reduced glutathione protects the brain and BBB from reactive oxygen species created in part by metal ions, such as aluminum. Aluminum is known to decrease the production of glutathione⁵⁷⁸. Reduced glutathione has been shown to be required for functional BBB integrity⁶⁷⁷. 

The permeability of the BBB can be decreased by supplementation of the following biochemicals and minerals that improve BBB integrity by either increasing glutathione in the brain or combating aluminum:

o   Biochemicals that Improve BBB Integrity by Increasing Glutathione⁶⁷⁷

·         Vitamin D²⁹⁶

·         N-Acetylcysteine (a.k.a. NAC) ⁶⁷⁷

o   Mineral Supplements that Maintain BBB Integrity by Combating Aluminum^670,678

·         Orthosilicic Acid⁶⁷⁸

·         Zinc⁶⁷⁰

Why Hemodialysis Patients Have High Levels of Serum Aluminum and a Low Risk of AD

There is a mystery as to why hemodialysis patients, who have high blood serum aluminum levels, not get Alzheimer’s disease. The solution is that orthosilicic acid can impede aluminum from crossing the BBB.  There are two reasons:

·        Aluminum must cross the BBB in order to cause Alzheimer’s disease. 

·        Hemodialysis patients have both higher than normal serum aluminum and orthosilicic acid. The orthosilicic acid impedes aluminum from crossing the BBB^679-683

Levels of Aluminum and Orthosilicic Acid in Serum and Cerebrospinal Fluid (CSF)
Serum and CSF	Aluminum (mcg/Liter)	Orthosilicic Acid (mcg/Liter)
Normal Kidney Function
Serum	<1	140 + 40 (140 + 14)
CSF	<1	235 + 49
Hemodialysis Patients
Serum	130 + 8	4220 + 630 (2190 + 132)
CSF	5 + 2	2580 + 300

           

Data is from Van Landeghem⁶⁸² except for data in parenthesis from Roberts⁶⁸⁰

The data in this table shows that even though aluminum is much higher than normal, it is 25 fold lower in the CSF as compared with serum of those on hemodialysis.  This shows that the BBB is working with orthosilicic acid to keep aluminum out of the brain. As the data in this table also shows, the level of orthosilicic acid is 15 fold higher than normal in the serum of those on hemodialysis. This results in chelation of the orthosilicic acid with aluminum forming non-lipophilic aluminosilicate that blocks aluminum from crossing the BBB. Since the kidneys of hemodialysis patients are not functioning correctly, aluminum, silicic acid, and aluminosilicate are not excreted by urination but are instead locally concentrated and deposited as aluminosilicates at the BBB.

In hemodialysis patients aluminum is found using laser microprobe mass analysis as deposits in the brain’s vascular system, cytoplasm of choroidal epithelium cells, astrocytes, and microglial cells⁶⁸⁴. These aluminum containing deposits behave chemically like aluminosilicate⁶⁸⁴ and are in a different location in the brain as compared with the aluminosilicate deposits found by x-ray microanalysis and nuclear magnetic resonance in the core of approximately 50% of Aβ plaques and neurofibrillary tangles that are seen as hallmarks of Alzheimer’s disease^685,686. This is because plaques and tangles are formed in and around neurons due to aluminum accumulation on the brain side of the BBB. High levels of serum orthosilicic acid impede aluminum from crossing the BBB by forming aluminosilicate that deposits on the blood side of the BBB.

The data in the table also shows that orthosilicic acid does cross the BBB as it is found at higher than normal levels in both the blood’s serum and brain’s CSF.  Even though a small but higher than normal amount of aluminum is found in the CFS of hemodialysis patients, the higher than normal level of orthosilicic acid in the CFS protects the brain from this small amount of aluminum that does cross the BBB.

Possibly because of a history of traumatic brain injury or vascular disease, the BBB in a small number of patients (i.e. 4%) on hemodialysis does fail to protect the brain from aluminum crossing from the blood to the brain and quickly accumulating in the brain⁶⁸⁷. These patients suffer from dementia due to aluminum encephalopathy that can be fatal.  This disease is much quicker to develop symptoms (i.e. 1 year or less) than Alzheimer’s that takes 5 to 20 years before the first symptoms of cognitive impairment are observed.  It is postulated that aluminum encephalopathy may involve aluminum altering brain calcium homeostasis by complexing with calmodulin⁶⁸⁸.  The toxicity of aluminum on the brain side of the BBB is underscored by two patients who underwent routine brain surgery requiring bone cement. These cements contain labile aluminum and fluoride⁶⁸⁹. After the operations their CSF had 63-112 mcg/Liter of aluminum. They never regained consciousness and died 80-143 days after their operations⁶⁹⁰.

Conclusion

The BBB working with orthosilicic acid protects the brain from aluminum preventing Alzheimer’s disease and aluminum encephalopathy.

Without being aware of the roles played by the BBB and orthosilicic acid in protecting the brain from aluminum, many scientists incorrectly drew the conclusion that aluminum does not cause Alzheimer’s because those on hemodialysis with high serum aluminum levels do not have the hallmarks of Alzheimer’s⁶⁹¹.  This incorrect conclusion has resulted in a tragic lack of funding for research on how to prevent aluminum from causing Alzheimer’s. Hopefully research efforts can be refocused while implementing a plan to prevent Alzheimer’s by keeping the BBB functioning with glutathione, eliminating aluminum intake, and increasing orthosilicic acid intake.

Daily supplements that can be taken to help the BBB by increasing glutathione and combating aluminum are:

·         Orthosilicic Acid

·         Vitamin D

·         Zinc – 15mg per day as an amino acid chelate

·         N-Acetylcysteine (a.k.a. NAC)  – 600mg per day