Title:“Connecting the Dots” from Blood Brain Barrier Dysfunction to Neuroinflammation and Alzheimer’s Disease
Volume: 11
Issue: 3
Author(s): Kenneth Maiese
Affiliation:
Abstract: One of the novel observations reported by Paul Ehrlich who later was awarded the Nobel
Prize in Medicine was the separate compartments that were present between the organs of
the body and the brain. Ehrlich was able to show that aniline dye injected into the arterial
system was able to color multiple organs, such as the heart and kidneys, but did not affect
the brain. When such an experiment was performed in a reverse mode years later with
injection of the dye into the cerebrospinal fluid of the brain by Ehrlich’s student, Edwin
Goldmann, the peripheral organs were noted to be unstained and without evidence of dye. These early experiments identified
the existence of the blood brain barrier (BBB) that may years later would be identified as a critical system that controls the flow
of agents to and from the brain as well as leading to brain pathology during dysfunction of the BBB system.
The BBB is composed of tight junctions that exist between endothelial cells in the central nervous system. Due to the highly
restrictive transport across the BBB, few drugs are able to pass through this barrier. Dependent upon the drug composition,
some estimates point to only 1% of drugs can pass the through the BBB and be active in the central nervous system. Agents that
pass though the BBB through diffusion must be lipid soluble, small in size (<400 Da), and have low hydrogen binding. Other
mechanisms that facilitate transport across the BBB include processes that involve carrier-mediated transport and receptor
mediated transport, such as the transport of insulin across the BBB.
Dynamics and functional stability of the BBB can become severely altered during disease states such as infection or
ischemic injury. For example, following a stroke, vascular reperfusion can ensue that results in the initial disruption of the
integrity of the BBB, subsequent leakage, and cerebral edema with concurrent neuronal cell loss. These processes also may lead
to hemorrhagic transformation following an ischemic stroke. Although these initial insults to the BBB may eventually be
repaired with restoration of endothelial tight junctions, it appears that activation of inflammatory pathways as well as other
toxic processes may be the primary culprits that are responsible for injury to the brain during the vulnerable period that occurs
with BBB dysfunction. However, even low-grade chronic BBB injury may result in neurodegenerative disease. In regards to
chronic neurodegenerative disorders such as Alzheimer’s disease, the brains of patients with Alzheimer’s disease have been
reported to show BBB leakage that was associated with the APOE4 allele, suggesting that BBB dysfunction may contribute to
the onset and/or progression of Alzheimer’s disease.
In this issue of Current Neurovascular Research, several novel studies are presented that focus upon the critical role that the
BBB and vascular disease may have during both acute and chronic neurodegenerative disorders. In the paper by Ning et al., the authors examine the role of cerebral microemboli during β-amyloid deposition in an amyloid precursor protein/presenilin 1
(APP/PS1) double transgenic mouse model of Alzheimer’s disease. The authors demonstrate that internal carotid artery
injection of microemboli can result in increased β-amyloid deposition that occurs during elevated matrix metalloproteinase-9
expression, suggesting that BBB injury may be a factor leading to the increased β-amyloid accumulation in the brain.
Interestingly, Provias and Jeynes illustrate that in the brains of Alzheimer’s patients, capillary vascular endothelial growth
factor is significantly reduced in the superior temporal, hippocampus and brainstem regions of the brain. Given the significant
role of vascular endothelial growth factor for endothelial cell viability and BBB maintenance, their work provides further
support for the premise that vascular disease in conjunction with BBB injury may be a contributory factor for the development
or progression of Alzheimer’s disease.
In conjunction with vascular injury, inflammatory disease also may be a significant factor that severely impacts
neurodegenerative cell injury. Barichello et al. use an experimental model of pneumococcal meningitis to examine
inflammatory parameters and BBB disruption. Following treatment with daptomycin or ceftriaxone, interleukin-4 and
neutrophil chemoattractant -1 were reduced with restoration of BBB integrity, suggesting that modulation of inflammatory
mediators may be necessary for the maintenance of BBB function. In related work, Yang et al. also point to a vital role for
inflammatory cell function. The authors show that in a murine model of chronic cerebral hypoperfusion that reduction in
microglial activation and inhibition of autophagy reduces the presence of white matter lesions and improves working memory,
suggesting that intact cognitive function may be closely tied to inflammatory cell activity.
The role of BBB damage during central nervous system injury is further highlighted in our review articles in this issue of
Current Neurovascular Research. Jin et al. discuss the role of early ischemic BBB damage during tissue plasminogen activatorassociated
hemorrhagic transformation and the ability to develop new therapeutic strategies to prevent hemorrhagic
complications during thrombolytic treatment for stroke. In the review article by Michels et al., the authors highlight the role of
microglia during sepsis in the central nervous system and describe the ability of these cells to generate cytokines and
chemokines, lead to oxidative stress, and result in BBB breakdown. Their work and analysis places a sharp focus on targeting
neuroinflammatory mechanisms for the development of new therapies against disorders in the nervous and vascular systems.
Our other review articles complement these papers by shedding light on the role of glycogen synthase kinase-3β (GSK- 3β)
during ischemic neuronal injury and the mechanisms and therapeutic options for the development of depression in individuals
who suffer a stroke. Pradeep et al. discuss a number of pathways in which GSK- 3β can mediate cell injury, such as through
oxidative stress, mitochondrial dysfunction, and activation of inflammatory mediators. All of these pathways including GSK-
3β have been implicated in not only neuronal cell injury, but also BBB dysfunction and cognitive loss. Nabavi et al. examine
the pathways that can lead to depression in stroke patients and provide insight into the potential anti-depressant role of reorganization of neural circuitry through brain derived neurotrophic factor (BDNF), an agent that can promote endothelial cell
survival, vascular growth, and maintenance of BBB integrity.
In this issue of Current Neurovascular Research, a number of novel and elegant studies highlight the critical role played by
the BBB in both health and illness. Yet, the link of BBB injury to several acute and chronic neurodegenerative disorders is not
always self-evident. Therefore, the ability to launch new therapeutic strategies that can either maintain or control BBB
permeability during disease states requires meticulous experimental analysis to correctly “connect the dots” from disorders of
the central nervous system to internal cellular pathways that govern the intricate system of cerebral endothelial cells tightly
linked together that comprise a selective gatekeeper for the brain known as the BBB.
