XU LABORATORY
INSTITUTE FOR CELL ENGINEERING
DEPARTMENT OF NEUROLOGY | JOHNS HOPKINS SCHOOL OF MEDICINE
Unraveling Blood–Brain Barrier Interface Dysfunction as a Driver of Brain Vulnerability and Cognitive Decline
Dynamic and complex interactions among endothelial cells, neurons, glial cells, and other components are essential for maintaining the homeostasis of the brain’s microenvironment. Disruption of this balance is increasingly recognized as a key contributor to cognitive decline in the aging population, particularly among genetically at-risk individuals.
Key Areas of Focus:
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Blood-Brain Barrier Dysfunction in Brain Vulnerability:
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The BBB is a selective barrier that regulates the passage of molecules between the bloodstream and the brain. In Vulnerable Brains, evidence suggests that BBB integrity is compromised, leading to increased permeability. This allows potentially harmful substances such as blood-derived proteins, inflammatory mediators, and immune cells to enter the brain, which can contribute to neuroinflammation, neuronal damage, and the progression of Brain Vulnerability.
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Amyloid-β Clearance Mechanisms:
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The BBB plays a critical role in the clearance of amyloid-β (Aβ) from the brain, a hallmark of Alzheimer's disease. Dysfunctional transport mechanisms at the BBB can lead to the accumulation of Aβ in the brain. Understanding how Aβ is transported across the BBB, and how these processes are altered in AD, can provide insights into therapeutic targets aimed at enhancing Aβ clearance.
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Neuroinflammation and the BBB:
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In Vulnerable Brains, chronic neuroinflammation is a significant factor that contributes to disease progression. The interaction between the BBB and the immune system is crucial, as BBB dysfunction can lead to an influx of peripheral immune cells into the brain, exacerbating neuroinflammatory processes. Studying the molecular and cellular changes at the BBB during neuroinflammation can help identify potential therapeutic targets to modulate immune responses in Vulnerable Brains.
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Vascular Contributions to Brain Vulnerability:
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Vascular dysfunction, including reduced cerebral blood flow and microvascular damage, is commonly observed in Vulnerable Brains. The BBB is a key regulator of vascular homeostasis, and its dysfunction can contribute to the vascular pathologies seen in Vulnerable Brains. Investigating how vascular changes influence BBB integrity and function in the context of Brain Vulnerability is essential for understanding the vascular contributions to Brain Vulnerability.
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Anatomical illustration of the blood-brain barrier interface
Study the BBB in Alzheimer's Disease
Strategies:
Advanced in vitro and in vivo models, including, brain organoids, brain microphysiological systems (brain-on-a-chip) and transgenic animal models, are essential tools for studying the BBB in the context of Alzheimer's disease. These models allow for the detailed investigation of BBB function, molecular interactions, and the effects of potential therapeutics in a controlled environment.
Therapeutic Strategies Targeting the BBB:
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Dissecting the BBB interface provides opportunities to develop therapeutic strategies aimed at restoring BBB integrity, enhancing Aβ clearance, and reducing neuroinflammation. Approaches may include the use of small molecules, antibodies, or gene therapy to target specific pathways involved in BBB dysfunction in Alzheimer's disease.
Many types of neurons
By dissecting the interface of the blood-brain barrier in the context of Cognitive Decline and Brain Vulnerability, researchers can gain a deeper understanding of the mechanisms underlying BBB dysfunction and its contributions to Cognitive Decline and Brain Vulnerability. This knowledge is critical for developing effective therapeutic strategies to protect and restore BBB function, ultimately aiming to slow or halt the progression of Cognitive Decline and Brain Vulnerability.