Reviewing Blood-Brain Barrier Dysfunction in the Context of Alzheimer's Disease

The biochemistry of the central nervous system is separated from the biochemistry of the rest of the body by the blood-brain barrier, a specialized lining of cells that wrap blood vessels that pass through the brain. Only some molecules and cells are permitted to pass into and out of the brain. Like all bodily systems, the blood-brain barrier breaks down with age, leading to leakage of unwanted molecules and cells into the brain, where they can provoke inflammation and dysfunction. This is thought to provide a significant contribution to the onset and further progression of age-related neurodegenerative conditions, given that blood-brain barrier failure appears somewhat in advance of other aspects of neurodegeneration in humans and animal models.

In today's open access paper, researchers review what is known of blood-brain barrier dysfunction specifically in the context of Alzheimer's disease. Relationships are observed between blood-brain barrier leakage and mechanisms involved in the production and aggregation of amyloid-β. Despite the failures of amyloid-β clearance to produce meaningful benefits in clinical trials, the build up of amyloid-β is still considered a core process in Alzheimer's disease, a foundational pathology that sets the stage for later, more severe pathology involving inflammation and tau aggregation leading to widespread cell death.

Reconsidering the role of blood-brain barrier in Alzheimer's disease: From delivery to target

The blood-brain barrier (BBB) is a dynamic interface that regulates the cellular communication between neural tissues and the blood and its constituents. It acts as a selective semipermeable barrier that controls the transport of substances to and from the central nervous system, serving as a key player in neural homeostasis. The blood is separated from central nervous system (CNS) by brain endothelial cells separated by tight junctions, adherens junctions, and gap junctions; pericytes; the foot processes of astrocytes, and the basement membrane composed of extracellular matrix components. Two main transport pathways occur within BBB: transcellular via endothelial cell used by the vast majority of the molecules which can be active (dependent on energy) or passive; and paracellular via passive diffusion through tight junctions.

The ubiquity and importance of BBB in CNS physiology also translate to how it is also impaired in almost every neurological condition. Such is the case of the most common cause of dementia, Alzheimer's disease (AD). AD affects more than 30 million people worldwide, a number that is expected to increase dramatically in the foreseeable future. To date, intracellular hyper-phosphorylated tau protein accumulation (neurofibrillary tangles) and extracellular amyloid-β (Aβ) deposition (senile plaques) in brain parenchyma is considered the central neuropathological hallmarks of the disease. However, pathogenesis is still not fully understood, and it is unclear whether these protein abnormalities are causative or rather incidental changes in the disease. Nevertheless, it is generally accepted that both proteins play a key role in disease pathogenesis with Aβ acting upstream of tau with other hypotheses building on and extending this to explain other aspects of the disease.

Aβ deposition seems to be a critical pathological trigger in AD and disruption of BBB leads to increased vascular permeability, allowing the entrance and/or hampering the clearance of toxic molecules that can trigger inflammatory and immune responses and, ultimately, neurodegeneration. One such pathologic protein whose normal clearance is dependent on a healthy BBB is the 42 amino acid Aβ peptide (Aβ42), considered the major toxic Aβ in AD. Not surprisingly, BBB dysfunction leads to Aβ deposition by disrupting its transporters. Moreover, there is experimental evidence that a disrupted BBB promotes its production from the amyloid precursor protein (APP) through the activation of the amyloidogenic pathway where APP is cleaved in sequence by β-secretase and γ-secretase.

Several studies have demonstrated BBB breakdown and dysregulation in AD. Whether it is a cause or consequence of the disease has been a matter of debate. Available evidence points to BBB breakdown as an early event preceding AD pathology. These findings have been supporting the vascular hypothesis of AD. First published in 1993 this hypothesis postulates that neurodegeneration is the consequence of a series of pathogenic pathways originating in blood vessels. More recently, others proposed the two-hit vascular hypothesis of AD. According to this hypothesis, impairment of blood vessels leads to BBB dysfunction and initiates a cascade of events leading to neuronal dysfunction (hit one). BBB dysfunction reduces Aβ clearance and increases its production inducing accumulation of this peptide, amplifying neuronal dysfunction, and accelerating neurodegeneration (hit two).

Blood-brain barrier has been emerging as a central hub for AD pathogenesis, presenting as a potential target to treat AD. Understanding its dysfunctional role in AD pathogenesis would be paramount for AD biology clarification and would probably give insights into other brain disorders. In this review, we will detail pathogenic and therapeutic links between AD and BBB offering a comprehensive and integrative view that includes the genetic landscape of AD and anticipates future research and treatment.

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