Is Blood-Brain Barrier Dysfunction Cause or Consequence in Alzheimer's Disease Pathology?
The blood-brain barrier is a layer of specialized cells wrapping blood vessels in the central nervous system, isolating the brain from the rest of the body by allowing on some cells and molecules to pass. The blood-brain barrier becomes leaky with age, however, as vascular dysfunction progresses. This allows inappropriate molecules into the brain to provoke inflammatory responses from brain-resident immune cells, and no doubt produces other detrimental consequences as well. Researchers do not consider it settled that blood-brain barrier dysfunction is a deeper cause of neurodegeneration, however. It may be at least in part a consequence of other aspects of neurodegenerative aging that take place in brain tissue.
Alzheimer's disease (AD) is a complex disorder that is clinically characterized by the progressive decline in cognition, and pathologically characterized by the accumulation of amyloid-β (Aβ) and phosphorylated tau (P-tau) in the brain. In recent years, a series of studies have demonstrated that AD is linked to blood brain barrier (BBB) dysfunction. BBB dysfunction has been identified in the early stage of AD. The BBB is a continuous membrane formed by a tightly sealed monolayer of endothelial cells. The main function of the BBB is maintenance of the brain health micro-environment by keeping neurotoxic components, pathogens, and circulating blood out of the brain.
The first clues regarding BBB dysfunction came from studies performed in AD genetic animal models with Aβ or tau pathology. Therefore, at that time, it was believed that BBB dysfunction was associated with Aβ or tau pathology. However, BBB breakdown and vascular dysregulation were also determined in preclinical and early-stage AD patients before cognitive decline or positive Aβ and tau pathology. These results suggested that the BBB breakdown that appeared in the early stage of AD could not be fully explained by the consequence of Aβ and/or tau pathology (the forms of plaques, tangles, and oligomers).
In recent years, emerging evidence has supported the contributions of neuroinflammation to AD pathogenesis. The associations between BBB breakdown and neuroinflammation have been explored in several studies. An injured BBB was associated with neuroinflammation such as microglial activation and elevated inflammatory cytokines release. However, the exact role of BBB dysfunction in AD pathogenesis is still unknown. It remains elusive whether BBB dysfunction is a consequence or a cause of Aβ pathology, tau pathology, neuroinflammation, or other conditions.