Blood–brain barrier endothelial cells in neurodegenerative diseases: Signals from the “barrier”

Abstract

As blood–brain barrier (BBB) disruption emerges as a common problem in the early stages of neurodegenerative diseases, the crucial roles of barrier-type brain endothelial cells (BECs), the primary part of the BBB, have been reported in the pathophysiology of neurodegenerative diseases. The mechanisms of how early vascular dysfunction contributes to the progress of neurodegeneration are still unclear, and understanding BEC functions is a promising start. Our understanding of the BBB has gone through different stages, from a passive diffusion barrier to a mediator of central-peripheral interactions. BECs serve two seemingly paradoxical roles: as a barrier to protect the delicate brain from toxins and as an interface to constantly receive and release signals, thus maintaining and regulating the homeostasis of the brain. Most previous studies about neurodegenerative diseases focus on the loss of barrier functions, and far too little attention has been paid to the active regulations of BECs. In this review, we present the current evidence of BEC dysfunction in neurodegenerative diseases and explore how BEC signals participate in the pathogenesis of neurodegenerative diseases.

Patient-Derived Blood-Brain Barrier Model for Screening Copper Bis(thiosemicarbazone) Complexes as Potential Therapeutics in Alzheimer’s Disease

“…Importantly, although brain endothelial cells are not the primary immune cells in the brain, they are known to participate in inflammatory responses at the brain barriers both in health and disease. ,− Correspondingly, a recent transcriptomic analysis revealed that many of the top AD-risk genes identified in genome-wide association studies (GWAS), which are microglia-specific in mice, are in fact expressed at higher levels in human BEC and other vascular cell types, suggesting that in mice and humans, there is a partial transfer of risk genes and pathways associated with AD from microglia to the vasculature during the process of evolution . This provides important evidence for the evolutionary-unique, human-specific role of BEC and cerebrovasculature in brain neuroimmunity in AD and justifies efforts of antineuroinflammatory drug candidate screening in BEC.…”

“…First, it presents a unique possibility to evaluate the antineuroinflammatory properties of novel compounds on the level of AD patient brain endothelial cells, previously not easily accessible to drug candidate screening efforts. With BBB neuroinflammation and neurodegeneration being closely linked in AD development and progression, , the discovery of such compounds may prove therapeutically useful in AD patients and lead to the identification of novel treatment avenues for AD.…”

“…Concurrently, recent studies have reported on multifactorial BBB dysfunction in AD, suggesting the involvement of BBB cells in disease development and progression. − In addition, neuroinflammation has been shown to drive some of the aspects of BBB impairment in AD linking multiple pathways involved in vascular- and neuro-degeneration. − Identified disease-associated changes at the BBB were also shown to contribute to the development of a complex microenvironment in AD brain barriers with important implications for drug delivery. − Together, these observations highlight the key limitation of traditionally used BBB models as they lack disease- and patient-specific characteristics, simultaneously urging the development of accurate BBB in vitro screening platforms to reliably model the response of AD patients to drug treatment.…”

Breaking the Barriers: Machine-Learning-Based c-RASAR Approach for Accurate Blood–Brain Barrier Permeability Prediction

“…2 The selective permeability of the BBB is orchestrated by tight junctions between endothelial cells, creating a daunting barrier that regulates the passage of ions, nutrients, and other essential substances crucial for proper brain function. 1,2 Understanding the intricacies of the BBB is pivotal not only for unraveling the mysteries of neurological health but also for developing targeted therapies for neurological disorders, as the barrier poses a formidable challenge for drug delivery to the brain. 1−4 The BBB plays a pivotal role in drug discovery, presenting both challenges and opportunities for researchers.…”

Experimental Models to Study the Functions of the Blood–Brain Barrier

“…Transport function is based on a few paths of penetration of the BBB by specific compounds, and these paths will be further reviewed later. It is commonly known that both described functions of this structure are impaired in cases of neurodevelopmental and neurodegenerative disorders, such as Alzheimer's Disease and amyotrophic lateral sclerosis [2,3]. According to recent studies, the loss of integrity of the BBB is a cause of neurodevelopmental disorders including autism spectrum disorder (ASD) [4] or schizophrenia [5].…”