Long term Cognition via a healthy intact Blood-Brain Barrier

Dr. Rhonda Patrick explains the blood-brain barrier.


Individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer’s Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau. Here is a discussion about this paper. By imaging the living human brain, Montagne et al. show an age-dependent blood-brain barrier (BBB) breakdown in the hippocampus, a region critical for learning and memory, which worsens with mild cognitive impairment and correlates with injury to BBB-associated cell pericyte.


Post-mortem tissue analysis indicates BBB damage in Alzheimer’s disease (AD). Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD.


A leaky BBB can result in fibrinogen entering the brain, where it can cause white matter disease, a common feature of Alzheimer’s.

Inflammation and neuroinflammation damages the blood-brain barrier

Neuroinflammation damaged the blood-brain barrier in rats. Neuroinflammation can cause the pericytes to shorten, creating a leaky BBB. Vascular cell adhesion molecule 1 (VCAM1) is the foremost biomarker of BBB dysfunction. The DHA fraction of fish oil may help. DHA (but not EPA) decreased, in a dose and time-dependent fashion, the expression of VCAM1. This blog post on neuroinflammation may be helpful.

Blood-Brain Barrier Overview: Structural and Functional Correlation

Pericytes and astrocytes maintain the blood-brain barrier (BBB). Keeping such cells healthy may be a matter of regular exercise and caloric restriction. Regular physical exercise diminishes BBB permeability as it reinforces antioxidative capacity, reduces oxidative stress and has anti-inflammatory effects. It improves endothelial function and might increase the density of brain capillaries.


Pericytes, SEM - Stock Image - C028/3861 - Science Photo Library



 It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis.


A study of the brains of mice shows that structural deterioration of the blood-brain barrier associated with old age can be prevented by long-term aerobic exercise starting in mid-life. Structural changes that make the blood-brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly.


Saturated fats and simple carbs – Oh, My!


HE (high levels of saturated fats and simple carbohydrates) consumption in rats produced a decrease in mRNA expression of tight junction proteins. Consequently, an increased blood-to-brain permeability was observed in the hippocampus following HE-diet access. These results indicate that hippocampal function may be particularly vulnerable to disruption by HE-diets, and this disruption may be related to impaired BBB integrity. Here is another similar rat study with the same conclusions.


Dr. Mike Hansen presented evidence for a leaky blood-brain barrier leading to cognitive decline in the video.
A diet with high levels of saturated fats and simple carbohydrates damaged the BBB in rats (this was also mentioned by Dr. Mike Hansen). The excessive consumption of dietary fats (fast food is culpable) triggers an inflammatory response in the hypothalamus promoting functional and structural damage of neurons involved in the regulation of food intake and energy expenditure. In addition to neuronal damage, excessive dietary fats disrupt the proper function of the blood-brain barrier (BBB).


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This rat study suggests that suggest that aluminum increases the permeability of BBB by changing its ultrastructure and the expression of occludin and F-actin. Zinc can protect the integrity of BBB in juvenile rats that are exposed to aluminum and inhibit the decrease of tight junction protein occludin and F-actin expression in BBB.


Short-chain fatty acids (SCFAs), mainly acetate, butyrate and propionate, produced by anaerobic bacterial fermentation of the dietary fiber in the intestine, have a key role in the communication between the gastrointestinal tract and nervous system and are critically important for the preservation of the BBB integrity under different pathological conditions.

7 Superfoods for Gut Health | Rose Wellness


A traumatic head injury can damage the blood-brain barrier. Mild traumatic brain injury alters the brain architecture and function; the BBB components are individually and collectively damaged.


Irisin protected the blood-brain barrier in rats subjected to abnormally low blood flow and excessive inflammation. Irisin is  secreted by the muscles during exercise.


There is an established body of work demonstrating that inflammatory signaling is mechanistically linked to changes in BBB function. Using lipopolysaccharide (LPS) as a inflammatory challenge, alterations in BBB permeability may involve a variety of key BBB regulatory mechanisms, including (i) direct damage to the endothelium; (ii) alterations in tight junction (TJ) expression and/or function that “loosen” adhesion of cells; and (iii) changes in glial (e.g., astrocytes, pericytes, microglia) function and quantity; and many other BBB regulatory mechanisms. This blog post on chronic inflammation is applicable.


The Circadian Rhythm and Sleep


Circadian rhythms modulate BBB integrity through regulating oscillations of tight junction proteins, assisting in functions of the neurovascular unit (NVU), and modulating transporter functions. More information on the circadian oscillation is in this blog post.


Sleep deprivation impaired the learning and memory ability and increased the levels of inflammatory cytokines, along with increased BBB permeability and activated astrocytes in hippocampus tissue.


REM sleep regulates the physical barrier properties of the blood-brain barrier.


Sleep restriction in rats decreased tight junction protein expression in microvessels and increased BBB permeability to low- and high-molecular weight tracers in in vivo permeability assays.


This study in mice showed that chronic sleep restriction decreased the functioning of the BBB.



Obesity is a BBB threat


In diet-induced obese mice, there is a loss of organization of the median eminence tanycytes (brain cells) resulting in a leakier barrier and an exacerbation of hypothalamic inflammation.


Effects of obesity and a high-fat diet on the BBB and the brain.
Effects of obesity on the BBB and the brain. Increased saturated fatty acids (SFA) concentration caused by high fat diet (HFD) or obesity enhance NF-κB-mediated inflammation at the BBB via TLR4 receptor. This causes increased leukocyte extravasation, release of pro-inflammatory cytokines, and activation of microglia. The hypothalamus is disrupted, leading to leptin and insulin insensitivity and greater obesity. Disruption of the hippocampus leads to cognitive impairment. Opening of the choroid plexus leads to enhanced leukocyte influx into the cerebrospinal fluid (CSF), more antigen sampling, and greater risk of immune response.


In the minute vasculature of the mouse hippocampus, the investigators saw that obesity first increased permeability of the blood brain barrier to tiny molecules like fluorophore sodium fluorescein, or NaFl. Diet-induced insulin resistance heightened that permeability so that a larger molecule, Evans Blue, which has a high affinity for serum albumin, the most abundant protein in blood, also could get through.


Cytoskeletal proteins play important roles in tight junction formation and function. Obesity downregulates cytoskeletal proteins at the BBB, including vimentin and tubulin (). Vimentin is involved in nutrient transport and energy metabolism by controlling the transport of low-density lipoprotein-derived cholesterol from the lysosome to the site of esterification (). The decreased levels of vimentin at the BBB could alter membrane fluidity preventing tight junction alignment in diet-induced obese mice. Tubulin is also involved in BBB transport and tight junction complex functions. The decreased levels of tubulin in the obese microvessels might be an indication of impaired BBB function.


Obesity also increases oxidative stress levels, which may contribute to BBB disruption as observed in diabetes and with systemic inflammation (). Studies have shown that high-intensity workouts in individuals who are obese lead to increased serum levels of S100β, a marker of BBB disruption (). In these obese patients, high-intensity workouts led to increased serum levels of reactive oxygen species and superoxide dismutase compared to non-obese exercised controls.



Rats infected the the bacterium that causes gingivitis developed and impaired BBB.


Years of high blood pressure can damage the BBB.


Bad news on alcohol


The use of psychostimulants and alcohol is known to affect the CNS and is implicated in various neurological disorders through neurotoxicity that partly results from increased BBB permeability. 


Alcohol causes the formation of gaps between BBB cells by tight junction disassembly, triggered by the endoplasmic reticulum and oxidative stress, highlighted by GRP78 chaperone upregulation and increase in reactive oxygen species production, respectively.


Blood-brain barrier integrity is the primary target of alcohol abuse - ScienceDirect


This mouse study indicates that the structural and functional proteins for BBB integrity may be the primary targets for the detrimental effects of alcohol abuse that lead to cognitive dysfunction and neurological deficits in high risk populations.

Aspartame is a BBB threat

This mouse study found that the intake of energy drinks, particularly the sugar free formulation, may compromise the integrity of BBB and induce neuroinflammation via hypotension, hyperglycaemia and inflammatory pathways.


This study of healthy adults found that aspartame also compromises the blood–brain barrier, increasing its permeability and altering concentrations of catecholamines, such as dopamine, in the brain. Thus, aspartame ingestion may have a role in the pathogenesis of certain mental disorders.


 This mouse study suggests an important toxic effect of elevated homocysteine (Hcy) on brain microvessels and implicates Hcy in the disruption of the BBB.


Oxidative stress will stress the BBB


Oxidative damage and disruption of the BBB is an emergent focus of neurodegenerative disease etiology and progression.


When the physiological balance between the generation and elimination of reactive oxygen species (ROS)/reactive nitrogen species (RNS) is disrupted, oxidative/nitrosative stress with persistent oxidative damage of the organism occurs. Oxidative stress has been suggested to act as initiator and/or mediator of many human diseases. The cerebral vasculature is particularly susceptible to oxidative stress, which is critical since cerebral endothelial cells play a major role in the creation and maintenance of the blood–brain barrier (BBB).


Since oxidative stress plays a significant role in the production and maintenance of the BBB, the cerebrovascular system is especially vulnerable to it. The pathways that initiate BBB dysfunction include, but are not limited to, mitochondrial dysfunction, excitotoxicity, iron metabolism, cytokines, pyroptosis, and necroptosis, all converging on the generation of ROS. Interestingly, ROS also provide common triggers that directly regulate BBB damage, parameters including tight junction (TJ) modifications, transporters, matrix metalloproteinase (MMP) activation, inflammatory responses, and autophagy.


This blog post on oxidative stress may help

Polychlorinated biphenyls disrupt blood–brain barrier integrity in mice.

Our findings to date show strong connections between PCBs and the health of astrocytes. They also contribute to our understanding of how crucial these astrocytes are to maintaining brain functioning. These star-shaped cells maintain the blood-brain barrier, support neurons, regulate communication between neurons, and repair nervous tissue following injury, among many other supportive tasks. 

By Otto

I am a health enthusiast, engineer, and maker.