The adult quiescent blood–brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/β-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Moreover, angiopoietin/Tie2 signalling that is linked to angiogenic processes has gained attention in the BBB field. Blood vessels play an essential role in initiation and progression of many diseases, including inflammation outside the central nervous system (CNS). Therefore, the potential influence of CNS blood vessels in neurological diseases associated with BBB alterations or neuroinflammation has become a major focus of current research to understand their contribution to pathogenesis. Moreover, the BBB remains a major obstacle to pharmaceutical intervention in the CNS. The complications may either be expressed by inadequate therapeutic delivery like in brain tumours, or by poor delivery of the drug across the BBB and ineffective bioavailability. In this review, we initially describe the cellular and molecular components that contribute to the steady state of the healthy BBB. We then discuss BBB alterations in ischaemic stroke, primary and metastatic brain tumour, chronic inflammation and Alzheimer’s disease. Throughout the review, we highlight common mechanisms of BBB abnormalities among these diseases, in particular the contribution of neuroinflammation to BBB dysfunction and disease progression, and emphasise unique aspects of BBB alteration in certain diseases such as brain tumours. Moreover, this review highlights novel strategies to monitor BBB function by non-invasive imaging techniques focussing on ischaemic stroke, as well as novel ways to modulate BBB permeability and function to promote treatment of brain tumours, inflammation and Alzheimer’s disease. In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) peptides and neurofibrillary tangles containing hyperphosphorylated neuronal tau protein. AD pathology is also characterized by chronic brain inflammation, which promotes disease pathogenesis. In this context, the blood-brain barrier (BBB), a highly specialized endothelial cell membrane that lines cerebral microvessels, represents the interface between neural cells and circulating cells of the immune system. The BBB thus plays a key role in the generation and maintenance of chronic inflammation during AD. The BBB operates within the neurovascular unit (NVU), which includes clusters of glial cells, neurons and pericytes. The NVU becomes dysfunctional during AD, and each of its components may undergo functional changes that contribute to neuronal injury and cognitive deficit. In transgenic animals with AD-like pathology, recent studies have shown that circulating leukocytes migrate through the activated brain endothelium when certain adhesion molecules are expressed, penetrating into the brain parenchyma, interacting with the NVU components and potentially affecting their structural integrity and functionality. Therefore, migrating immune system cells in cerebral vessels act in concert with the modified BBB and may be integrated into the dysfunctional NVU. Notably, blocking the adhesion mechanisms controlling leukocyte-endothelial interactions inhibits both Aβ deposition and tau hyperphosphorylation, and reduces memory loss in AD models. The characterization of molecular mechanisms controlling vascular inflammation and leukocyte trafficking could therefore help to determine the basis of BBB dysfunction during AD and may lead to the development of new therapeutic approaches.