Dysfunction of the Blood-Brain Barrier-A Key Step in Neurodegeneration and Dementia

Abstract

The vascular endothelium in the brain is an essential part of the blood-brain-barrier (BBB) because of its very tight structure to secure a functional and molecular separation of the brain from the rest of the body and to protect neurons from pathogens and toxins. Impaired transport of metabolites across the BBB due to its increasing dysfunction affects brain health and cognitive functioning, thus providing a starting point of neurodegenerative diseases. The term "cerebral metabolic syndrome" is proposed to highlight the importance of lifestyle factors in neurodegeneration and to describe the impact of increasing BBB dysfunction on neurodegeneration and dementia, especially in elderly patients. If untreated, the cerebral metabolic syndrome may evolve into dementia. Due to the high energy demand of the brain, impaired glucose transport across the BBB via glucose transporters as GLUT1 renders the brain increasingly susceptible to neurodegeneration. Apoptotic processes are further supported by the lack of essential metabolites of the phosphocholine synthesis. In Alzheimer's disease (AD), inflammatory and infectious processes at the BBB increase the dysfunction and might be pace-making events. At this point, the potentially highly relevant role of the thrombocytic amyloid precursor protein (APP) in endothelial inflammation of the BBB is discussed. Chronic inflammatory processes of the BBB transmitted to an increasing number of brain areas might cause a lasting build-up of spreading, pore-forming β-amyloid fragments explaining the dramatic progression of the disease. In the view of the essential requirement of an early diagnosis to investigate and implement causal therapeutic strategies against dementia, brain imaging methods are of great importance. Therefore, status and opportunities in the field of diagnostic imaging of the living human brain will be portrayed, comprising diverse techniques such as positron emissions tomography (PET) and functional magnetic resonance imaging (fMRI) to uncover the patterns of atrophy, protein deposits, hypometabolism, and molecular as well as functional alterations in AD.

Keywords: Alzheimer’s disease; GLUT1; amyloid precursor protein (APP); blood-brain barrier (BBB); dementia; glucose; inflammation; positron emission tomography (PET).