Disease-specific BBB Dysfunction

The blood brain barrier (BBB) is an essential interface between the circulatory system and the brain that governs the progression of central nervous system (CNS) diseases. Yet, its complex biology and mutable nature challenge researchers to unravel its intricacies and cast light on disease-specific BBB dysfunction. At Creative Biolabs, we are committed to empowering research in this field by providing comprehensive solutions for studying BBB function and dysfunction.

Understanding the BBB

The BBB comprises endothelial cells lining the brain microvessels, astrocyte end-feet, pericytes, and a basement membrane, jointly referred to as the Neurovascular Unit (NVU). It tightly regulates the movement of ions, molecules, and cells between the blood and the brain.

Fig. 1 Schematic representation of the BBB.¹

The BBB is an indispensable component of homeostasis in the CNS, as it controls nutrient intake, waste product elimination, and the neuro-immune axis. However, BBB dysfunction leads to a compromised NVU, culminating in considerable neuronal damage and the progression of debilitating conditions like Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, and brain malignancies.

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BBB Dysfunction in Neurological Disorders

Understanding the mechanisms underlying disease-specific BBB dysfunction is crucial for developing targeted therapeutic interventions.

Alzheimer's Disease (AD)
Recent studies shed light on the role of BBB dysfunction in AD's pathogenesis. Microvascular degeneration, endothelial cell degradation, and reduced expression of BBB-specific transporters often cause the BBB to fail to clear amyloid proteins, enabling their unhealthy buildup in the brain. Furthermore, a weakened BBB allows unwanted agents, like neurotoxins and peripheral immune cells, to enter the CNS and exacerbate neuroinflammation and neuronal death.

Parkinson's Disease (PD)
PD also involves BBB alterations that may contribute significantly to its pathogenesis. For instance, the disrupted BBB in PD patients allows more peripheral levodopa to cross into the brain, subsequently converted into dopamine. However, an excess influx of peripheral levodopa can ultimately lead to levodopa-induced dyskinesia, a common motor complication in PD.

Stroke
Stroke is a vascular disorder where BBB dysfunction plays a crucial role in its course and outcomes. Following a stroke, the BBB suffers heightened permeability due to oxidative stress, inflammatory response, and the secretion of vascular endothelial growth factors. This results in the influx of blood components and potential pathogens, thereby contributing to edema, secondary injury, and poor prognosis. Furthermore, post-stroke BBB disruptions may pave the way for hemorrhagic transformation and thrombolytic-associated brain hemorrhages, significantly raising the mortality risk.

Inflammatory Disorders
In MS, the immune system mistakenly attacks the protective covering of nerve fibers, resulting in inflammation. This inflammatory response compromises the BBB, enabling immune cells to infiltrate the brain and exacerbate the damage, contributing to the progression of the disease.

Fig. 2 BBB in health and during inflammation.²

Mechanisms of BBB Dysfunction

Several common pathways contribute to BBB disruption across different diseases.

Pathways	Mechanisms that Destroy the BBB
Inflammation	Chronic inflammation is a common denominator in many diseases associated with BBB dysfunction. Inflammatory mediators, such as cytokines and chemokines, can directly compromise tight junction integrity and promote increased permeability.
Oxidative Stress	Elevated levels of oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) and antioxidants, contribute to BBB dysfunction. Oxidative stress can damage endothelial cells and disrupt the delicate balance required for BBB integrity.
Protein Aggregation	In neurodegenerative diseases, the accumulation of misfolded proteins not only contributes to neuronal damage but also directly impacts the BBB. Disrupted protein homeostasis can trigger cellular stress responses, further compromising the barrier's function.
Matrix Metalloproteinases (MMPs)	MMPs are enzymes involved in the breakdown of extracellular matrix components. In various diseases, including stroke and TBI, increased MMP activity has been linked to BBB disruption. MMPs can degrade tight junction proteins, leading to increased permeability.

Implications for Therapeutics

Understanding disease-specific BBB dysfunctions can guide therapies' development by identifying new molecular targets, informing drug design, and paving the way for innovative drug delivery strategies.

Enhancing BBB Integrity
Therapies aimed at stabilizing the BBB can potentially reduce neuro-inflammation and neuronal death. Several approaches are underway to enhance BBB integrity using anti-inflammatory agents, endothelial protection agents, and pericyte stabilization agents. Their central goal is to minimize the passage of harmful agents across the BBB and protect the CNS from further damage.

Modulating BBB Permeability
Strategies are also being examined to increase the BBB's selective permeability temporarily to deliver therapeutic agents. This can be achieved through receptor-mediated transcytosis, utilizing endogenous transporters or even by using disruptive methods like focused ultrasound or BBB permeabilizing agents.

Drug delivery through the BBB
Effective drug delivery to the brain remains an exceedingly difficult challenge due to the BBB. Currently, nano-engineered particles, liposomal carriers, antibody-drug conjugates, and cell-penetrating peptides are gaining traction. Additionally, advances in pharmaceutical biotechnology have shown promise in developing disease-modifying treatments and targeted drug delivery systems.

Future Directions of BBB-Dysfunction Research

As we deepen our understanding of disease-specific BBB dysfunctions, it is increasingly clear that the BBB is more than a passive barrier - it's an active player in neurological disorders. Studying the BBB in health and disease is expected to offer insights into disease progression and therapeutic potential. At Creative Biolabs, our cutting-edge neuroscience research tools and dedicated services aim to partner in this quest.

References

Keaney, et al. "The dynamic blood–brain barrier." The FEBS journal 282.21 (2015): 4067-4079.
Galea, Ian. "The blood–brain barrier in systemic infection and inflammation." Cellular & Molecular Immunology 18.11 (2021): 2489-2501.

For Research Use Only. Not For Clinical Use.