The Blood-Brain Barrier and its Role in Neurodegenerative Diseases

Neurodegenerative diseases are a group of devastating disorders that result in a gradual decline of cognitive function, movement control, and various other important neurological processes. Millions of people across the world suffer from these diseases, placing a significant burden on healthcare systems, caregivers, and economies. As populations and life expectancies increase, the prevalence of these conditions continues to rise.

Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are among the most common of the diseases that fall under this umbrella and, despite their difference in disease etiology and treatment, the degenerative nature and some downstream effects of each disease are relatively similar. (2) 

While understanding the specific genetic and/or biological mechanisms that cause each disease is essential, understanding the common consequences (such as tissue damage and immune response) and how they contribute to disease progression can be equally important. This article is meant to discuss one of the consequences that neurodegenerative diseases share: dysfunction of the blood-brain barrier (BBB).

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What is the BBB?

The BBB is a physical weapon designed by your body specifically to protect your most important and irreplaceable organ – your brain! Just as a guard monitors and filters people entering a restricted area, the BBB is highly selective about which molecules, ions, and cells are allowed to enter the brain from the bloodstream.

While most organs in the body have barriers to protect against potentially harmful things in the bloodstream, the barrier in the brain is superior. The BBB consists of 3 different cell types (endothelial cells, pericytes, and astrocytes) along with membranes (a matrix), which work as a team to line the blood vessels in the brain and create the most selective barrier in your body. (3, 4)

What is its purpose? 

The BBB is working to protect your brain 24/7, but it is especially important in times of illness. For example, viruses and bacteria can circulate in the bloodstream. Without the BBB, these pathogens can enter the brain and wreak havoc on the brain’s well-maintained homeostasis, causing encephalitis (inflammation of the brain), meningitis (inflammation of the membranes surrounding the brain and spinal cord), or interrupting other neurological systems. 

This selective permeability of the BBB is vital in maintaining the overall health and function of the central nervous system (CNS). 

BBB Damage

Similar to a security breach, which compromises the safety of a protected area, damage to the BBB allows for increased permeability into the brain, leaving the brain vulnerable to harmful substances circulating in the bloodstream. The BBB can become damaged for various reasons. In neurodegenerative diseases, though, the most common reasons include:

Inflammation: 

Immune cells in the brain produce various signals called cytokines and chemokines in response to the disease pathology. These signals trigger inflammation and can induce changes in the cells that make up the BBB. (6)

Oxidative Stress: 

This type of stress occurs when there is an imbalance in reactive oxygen species (ROS) and the body’s ability to detoxify them. (7) 

ROS are highly reactive molecules that directly damage important cellular components, including cell membranes, proteins, and DNA. 

Disease Pathology: 

The specific mechanisms of each neurological disease can play a large role in the dysfunction of the BBB. Amyloid-β (Aβ), one of the major proteins involved in AD, can directly interact with and damage the endothelial cells that make up the BBB.

Aging: 

As with neurodegenerative diseases, BBB damage can also occur naturally with aging in the absence of underlying conditions. (9)

Consequences of BBB Damage

Once the BBB is damaged, the following consequences only exacerbate the disease pathology. What was once a protective barrier can then allow harmful agents to infiltrate the brain, leading to various downstream effects.

Immune Cell Infiltration

Chronic neuroinflammation is a major consequence of BBB damage. The brain is often referred to as an “immune privileged” site. This means that the brain has its own immune cells, which are separate from the peripheral body, enabling the brain to have high control over immunity and inflammation. (10)

When the BBB is compromised, immune cells from the body can infiltrate the brain in response to the various signals produced from the disease (i.e., signals released from cell death or damage), where they contribute to inflammation and cause further damage. (11)

Toxin Accumulation

With increased permeability, toxic substances that are normally kept out of the brain can accumulate. These toxins can include heavy metals, environmental pollutants, and metabolic waste products. Their presence can contribute to neuronal injury and cell death. (9)

Impaired Nutrient Delivery

The BBB plays a crucial role in regulating the transport of essential nutrients, such as glucose, amino acids, vitamins, and minerals, from the bloodstream into the brain. 

When the BBB is compromised, either due to dysfunction or damage, the delivery of nutrients to the brain can be impaired in several ways at the endothelial cell receptor and transporter level, the major players in biomolecules and nutrient transportation. (12)

Neuronal Damage

While neurodegenerative diseases cause neuronal damage and cell death through their own pathology, damage to the BBB elevates this. As a result of the above consequences, inflammation and toxin accumulation directly impact neuronal cell health. 

How to Protect Your BBB

Because BBB dysfunction can happen naturally with age, maintaining a healthy lifestyle is the best course of action to strengthen your BBB. Eating healthy meals, exercising regularly, managing stress, achieving adequate amounts of sleep, and limiting drug and alcohol consumption can all help to protect your BBB from damage. (13, 14)

Eating foods that are rich in omega-3 fatty acids can also aid in BBB protection. Studies have shown significant correlations between omega-3-fatty acid foods and BBB integrity likely attributed to their potent anti-inflammatory effects and support of vascular health by maintaining endothelial cell function, the cells that line the BBB. 

Identifying BBB Damage

While BBB dysfunction is presumed and treated in neurodegenerative disorders, there are ways to test BBB permeability. These technologies are particularly useful for disease monitoring. 

Advanced Imaging Studies

Advanced brain imaging techniques, such as magnetic resonance imaging (MRI) can detect structural changes in the brain associated with BBB damage. (16) 

When used in combination with dyes that are injected into the bloodstream, commonly called dynamic contrast-enhanced MRI (DCE-MRI), BBB permeability can be visualized and measured. When these dyes cannot pass a healthy BBB, leakage of these dyes into the brain indicates BBB damage.

A similar technique with computer tomography (CT) has also been shown to be successful. These techniques can be challenging, though, since BBB leakage tends to be subtle despite its disastrous effects.

Lab Testing

Examination of cerebrospinal fluid (CSF) can provide insights into BBB function and integrity. Elevated levels of proteins, such as albumin or immunoglobulins, in the CSF compared to blood can indicate BBB dysfunction. (19) 

Albumin concentration is typically high in the blood and low in CSF; however, during BBB damage, albumin can enter the brain during BBB damage, increasing the concentration of albumin in the CSF. (20)

Similarly, immunoglobulins, which are typically found in the blood, can have various effects once crossing into the CNS. (21)

Blood biomarkers can also indicate BBB disruption or neuroinflammation. For example, elevated levels of matrix metalloproteinases (MMPs) or cytokines in the blood may suggest BBB damage. (22, 23)

In some cases, a brain biopsy may be performed to directly assess BBB integrity and identify pathological changes associated with BBB dysfunction. This method is invasive and is typically reserved for cases where other diagnostic methods are inconclusive.

Treatment and Challenges

Treating BBB damage will depend on the underlying causes (e.g. disease etiology), reducing inflammation, and promoting repair of the barrier. This can be achieved through therapeutic intervention as well as lifestyle modifications. 

Anti-Inflammatory Therapy

Because inflammation plays a major role in BBB damage, the use of anti-inflammatory drugs is often a first line of defense when choosing a treatment route. Targeting the neuroinflammatory aspect of BBB damage can promote tissue repair and help restore the barrier. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressive drugs are the most common. (25)

Neuroprotective Agents

Certain medications or supplements with neuroprotective properties may help to support BBB repair and prevent further damage. This includes omega-3 fatty acids and polyphenols. (26)

Blood Pressure Management

High blood pressure can contribute to BBB damage through vascular stress and promoting inflammation. Monitoring and treating blood pressure accordingly can help to slow or prevent further damage. (27)

Managing Underlying Conditions

Treating the neurological disorder itself helps to alleviate BBB dysfunction by targeting the damage at its source. Medical interventions vary for each disease.

Ongoing Research

Because of the impact that BBB damage has on brain inflammation and neurodegeneration, research is underway to develop therapies that can promote BBB repair. Emerging studies have demonstrated success in therapeutics that target frizzled (FZD) receptors and the Wnt pathway. (29) 

While repairing the BBB may not cure neurodegenerative diseases, it may be possible to help slow disease progression and improve side effects.

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Key Takeaways

Overall, BBB dysfunction is increasingly recognized as a significant factor in the pathogenesis of neurodegenerative diseases. 

Understanding the mechanisms underlying BBB dysfunction and developing strategies to preserve or restore BBB integrity may hold promise for the prevention and treatment of these devastating conditions.