Episode # 16
The Alzheimer's Solution Revolution
#16—Brain Detoxification-Part 1-The Role of the Blood Brain Barrier and The Glymphatic System
Read More
EPISODE 5
Summary and Audio
Hello and welcome to episode #16!
This is Ralph Sanchez and today I’ll be describing an elemental aspect in maintaining a healthy brain as you age, and preventing the cognitive decline that is associated with unhealthy aging, and the risk for Alzheimer’s disease—brain detoxification.
Because brain detoxification mechanisms are a very complex review, I will provide it in three parts–this episode (part 1), and the next two.
Now, most people that are oriented toward health and wellness strategies know that a good detox for their body is one of the more healthful things one can do for their wellbeing.
But what about your brain?
Well, there are also several key brain detoxification mechanisms that are often overlooked, or not emphasized enough.
And while detoxification programs and kits are extremely popular, the majority of detox programs I know of barely mention or address the challenge of brain detoxification.
This episode (part 1), will focus on the importance of a system of brain detoxification pathways and mechanisms that are vital to brain health and in risk reduction for late-onset Alzheimer’s disease (LOAD)—the blood brain barrier (BBB), and the glymphatic system.
The glymphatic system is now considered to contribute approximately 60% of the brain’s beta-amyloid drainage to the cervical lymph nodes, and further downstream into systemic circulation.
Both the glymphatic system and BBB are interconnected AND interdependent systems in the clearance of metabolic waste and neurotoxic proteins that are associated with Alzheimer’s disease (AD)—beta-amyloid and tau protein—the two proteins that can accumulate and form the hallmark plaque and tangle lesions associated with AD in the brain.
The glymphatic system was first described in a paper published 2012 by Dr. Maiken Nedergaard and his team at the University of Rochester Medical Center.
Since then, many studies have investigated the workings of the glymphatic system and all the moving parts associated with it.
So, let’s go over what the glymphatic system is … it is often described as a lymph-like network, and up until it’s discovery in 2012, the conventional wisdom held that there were not any lymphatic vessels in the brain as there are in the body.
However, there is a lymphatic system that is integrated within the glymphatic system—the meningeal lymphatics which I describe in this episode.
In short, the glymphatic system is composed of several essential parts that include the meningeal lymphatics to make it a functional apparatus that is essential in brain detoxification.
To paint a picture in your mind of these related systems, the glymphatic system is where toxic protein and other waste material is collected and eventually drained into the blood stream, AND that waste is also exported into the meningeal lymphatic system and to the cervical lymphatic vessels and nodes which lie deep in the neck area.
So, there are two exit routs for the glymphatic waste fluid—the blood and the meningeal lymphatics.
In the next episode (part 2 of this brain detoxification series), I’ll describe what happens next to this metabolic waste once it is exported from the brain and into peripheral circulation.
In the meantime, listen in to the podcast audio below, which includes many more details on the lymph and glymph systems that are a vital component in detoxifying the toxic proteins—beta-amyloid and tau protein—across the blood brain barrier for elimination
Top Takeaways
• The glymphatic system, discovered in 2012, is a glial-dependent (astroglia) waste clearance network, which in part is composed of astrocytes, their aquaporin-4-lined endfeet which wraps around the blood vessels (capillaries) coursing through the brain, and pericytes (see post image at the top of the page).
In addition, the paravascular spaces—the fluid filled space that surrounds the capillaries, and where cerebrospinal fluid mixes with interstitial fluid (fluid-filled spaces between brain cells)—serves as a conduit to clear beta-amyloid and tau protein from the brain.
• The neurovascular unit, composed of astrocytes, pericytes, neurons, and cerebral vasculature (capillaries), describes the functional and structural elements of blood brain barrier (BBB), and it’s interface with the central nervous system.
• The glymphatic system accounts for roughly 60% of beta-amyloid drainage from the brain, ultimately exporting waste through two routes: the bloodstream and the meningeal lymphatics, a lymphatic network in the brain’s meninges* that was only recently discovered.
* The meninges are composed of three thin layers of tissue (Dura Mater, Arachnoid Mater, Pia Mater) that surround and protect the brain and spinal cord.
• Cerebral small vessel disease (cSVD), marked by white matter hyperintensities and lacunar strokes, impairs blood flow needed to drive glymphatic clearance; deep white matter hyperintensities are detectable in 87% of people by age 70 and can appear as early as midlife.
• A set of transporters and receptors at the blood brain barrier (BBB) work in concert to transport and clear beta-amyloid through the BBB, and out of the brain.
• After the clearance across the BBB and into the peripheral circulation, beta-amyloid is normally destined for detoxification in the liver.
• The P-glycoprotein (P-gp/ABCB1) transporter, and LRP1 receptor (Low-density lipoprotein receptor-related protein 1) combine to clear beta-amyloid across the BBB.
• Notably, hyperglycemia (elevated blood glucose) in diabetes suppresses LRP1 expression, which leads to beta-amyloid accumulation in the brain.
• The clusterin (APOJ)* transporter and LRP2 receptor (Low-density lipoprotein receptor-related protein 2), also coordinate the clearance of beta-amyloid from the brain.
*The clusterin/APOJ gene is considered the third most significant genetic risk factor for late-onset
Alzheimer’s disease.
• As critical as the transport and clearance of toxic proteins (beta-amyloid, tau protein) across the BBB and into systemic circulation (brain to blood) is, it is just as important to prevent their transport back across the BBB, and into the central nervous system by similar mechanisms associated with their efflux out of the brain.
• ApoE4 carriers are more susceptible to BBB breakdown independent of beta-amyloid build up in the brain, which is driven by chronic proinflammatory insults such as activation of the pro-inflammatory protein Cyclophilin A.
Cyclophilin A damages and disrupts the functional and structural integrity of the BBB via a proinflammatory signaling pathway—the Cyclophilin A-NF-kB-MMP9 pathway; in contrast, the ApoE3 variant suppresses this pathway.
• A damaged and leaky BBB is linked to the wear and tear of the aging process, chronic systemic inflammation patterns (e.g., cardiometabolic disease), oxidative stress, and cerebral small vessel disease (cSVD).
Furthermore, chronic neuroinflammation associated with beta-amyloid and tau aggregation further impairs the structural integrity of the BBB, creating a self-reinforcing cycle of vascular and neurodegenerative damage to the BBB.
• Polyphenols, curcuminoids, carotenoids, and sulforaphane activate the Nrf2-ARE signaling pathway, inducing over 300 genes involved in detoxification, antioxidant defense, and anti-inflammatory protection that helps repair BBB damage from diabetes, cardiovascular disease, hypertension, and mini-strokes.
• Folate, B12, B6, choline, and betaine are integral nutrients in keeping homocysteine levels in check—elevated homocysteine (hyperhomocysteinemia) is an independent risk factor for cardiovascular disease, stroke, and impaired blood-brain barrier function.
• Vitamin D supports BBB integrity by regulating LRP1 transporter expression, promoting structural proteins, including occludin, claudin-5, and ZO-1, and inhibiting the Cyclophilin A-MMP9 inflammatory pathway; magnesium similarly increases LRP1 expression and reduces BBB permeability.
• Melatonin protects the BBB through antioxidant and anti-inflammatory action, suppressing NF-kB and MMP9 activity associated with inflammation, while butyrate, a short-chain fatty acid from bacterial fermentation of dietary fiber, has been shown to restore BBB integrity after traumatic brain injury.
• The glymphatic system is most active during non-REM stage 3 (deep/delta) sleep and following exercise; poor sleep and sleep deprivation are linked to buildup of both beta-amyloid and tau protein.
• Chronic stress and elevated cortisol damage the vascular system and hippocampus while disrupting sleep, compounding BBB breakdown; stress-modification practices such as yoga, tai chi, qi gong, and meditation, alongside consistent sleep and exercise, help protect both the BBB and glymphatic function.
Epidsode 16
Timestamp Highlights
In this Episode
[00:00:39] Introduction to this brain detoxification three-part series, and in this Part 1 episode, “The Role of the Blood Brain Barrier and The Glymphatic System”.
[00:03:32] Origins of the glymphatic system (a toxic protein and waste disposal system) concept from Dr. Maiken Nedergaard’s 2012 seminal research, and its link to newly discovered meningeal tissue (a 3 layered membrane that surrounds the brain and spinal cord) lymphatic vessels.
[00:05:03] The composition of the glymphatic system, including the role of astrocytes and the neurovascular unit (composed of a neuron-astrocyte-blood vessel and blood brain barrier interface) in forming the glial-dependent waste clearance pathway of the glymphatic system (glial cells are brain cells composed of microglia, astrocytes, and oligodendrorocytes).
[00:08:06] Astrocytic endfeet and pericytes, or mural cells, form an integral component of the blood brain barrier, and maintain blood brain barrier structure (BBB) and function (pericytes are specialized cells that surround the outer layer of the brain’s blood vessels—the capillaries). See poblog image at the top of this page.
[00:10:18] The paravascular space (the fluid filled space between the capillaries and astrocytic endfeet), and the so-called water channels aquaporin 4 (AQP4) which are integrated with the astrocytic endfeet, combine with the cerebrospinal and interstitial fluid to flush waste through brain tissue.
[00:13:17] The glymphatic system drains most of the brain’s beta-amyloid protein into the bloodstream and meningeal lymphatics—the two key toxic protein and waste exit routes.
[00:15:15] Introduction to the blood brain barrier’s role in regulating nutrient and toxin flow, and its breakdown with aging and small vessel (capillaries) disease.
[00:16:58] Cerebral small vessel disease ( e. g., atherosclerosis or beta-amyloid protein buildup) and white matter lesions (damaged area of the brain’s white matter) are key factors that impair the integrity of the glymphatic waste clearance.
[00:22:32] An overview of BBB transporters, including P-glycoprotein as a key BBB efflux transporter that removes toxins and beta-amyloid, and how amyloid buildup can disrupt its function.
[00:25:41] LRP1’s (low-density lipoprotein receptor-related protein 1) role as the main receptor mediating beta-amyloid clearance at the BBB, and how diabetes suppresses its expression.
[00:27:38] Additionally, the role of LRP2 and clusterin’s (or apolipoprotein J) in binding and clearing beta-amyloid. The clusterin gene is considered by many researchers to be the third most predominant genetic risk factor associated with late-onset Alzheimer’s disease.
[00:29:39] How the ApoE4 genetic variant drives BBB dysfunction through activation of the pro-inflammatory pathways and pericyte damage.
[00:33:09] Nutritional strategies for repairing the BBB and glymphatic system, highlighting polyphenols such as curcuminoids that activate the Nrf2 pathway.
[00:35:50] The importance of the Nrf2 pathway (Nrf2/ARE Pathway) in the induction of antioxidant and detoxification effects, and how B vitamins help regulate homocysteine to protect blood brain barrier function.
*The transcription factor, Nfr2, induces antioxidant and detoxification gene expression and protects against the overactivation of Nf-κB and chronic inflammation responses. The two transcription factors, Nfr2 and Nf-κB respectively, are core yin and yang regulators of anti-inflammatory/antioxidant and pro-inflammatory pathways.
[00:37:45] Additional compounds, including Chinese herbal extracts, melatonin, vitamin D, magnesium, and butyrate, that support blood brain barrier integrity.
[00:40:43] A brief recap of the effectiveness of a cardioprotective diet and lifestyle, which supports the integrity of the BBB, and the glymphatic system.
[00:41:24] Exercise and deep non-REM sleep as essential drivers of glymphatic clearance, and how poor sleep contributes to beta-amyloid and tau protein accumulation in the brain.
[00:43:18] Chronic stress and cortisol’s damaging effects on the BBB and hippocampus, and stress-reduction practices that protect brain health.
Please listen in!
Ralph Sanchez, MTCM, CNS, D.Hom
BrainDefend®
www.facebook.com/TheAlzheimersSolution
Omega-3 Test
Professional Supplement Store
Vitamin D Test
Omega-3 Index Plus Test
Omega-3 Test
Professional Supplement Store
Vitamin D Test
Omega-3 Index Plus Test
