Elsevier

Neurobiology of Disease

Volume 107, November 2017, Pages 57-65
Neurobiology of Disease

Review
Inflammation at the blood-brain barrier: The role of liver X receptors

https://doi.org/10.1016/j.nbd.2016.09.015Get rights and content

Abstract

The blood-brain barrier (BBB) is indispensable for the maintenance of brain homeostasis and proper neuronal functioning. Dysfunction of the BBB significantly contributes to the pathogenesis of neuroinflammatory and neurodegenerative diseases like stroke, multiple sclerosis (MS), and Alzheimer's disease (AD). The neuroinflammatory environment that characterizes these disorders propagates chronic impaired function of the BBB, processes that will be discussed in this review. Limiting dysfunction of the BBB may be an attractive target for treatment of neurological disorders. To date, no current treatments are directly targeting the function of the BBB. In this review, we will specifically discuss the potential protective role of nuclear liver X receptors (LXRs) as a promising therapeutic target to reverse or prevent BBB impairment in neurological diseases.

Section snippets

The blood-brain barrier

The blood-brain barrier (BBB) is responsible for maintaining brain homeostasis by controlling the environment of the central nervous system (CNS), the entry of nutrients, and by protecting it against xenobiotics. The physical barrier is formed by specialized endothelial cells, which have unique properties. Brain endothelial cells exhibit low pinocytotic activity and are sealed with adherens junctions (AJs) like VE-cadherin and E-cadherin that are connected to the cytoskeleton via catenins.

The BBB in neuroinflammatory diseases

In numerous pathological conditions of the CNS, including ischemic stroke, multiple sclerosis, and Alzheimer's disease, neuroinflammation contributes to the progression of clinical symptoms and may lead to neurodegeneration. Moreover, a dysfunction of the BBB is associated with these disorders. BBB dysfunction is characterized by endothelial cell junctional alterations and increased permeability. This can be induced by inflammation and vasoactive compounds in a disease-specific manner and

BBB alterations in neuroinflammation: cellular changes

The tight regulation of BBB function and its specific interactions with the environment ensures the preservation of CNS homeostasis. As mentioned, BBB dysfunction during disease can involve disruption of TJs, increase in transcytosis, changes in transport properties, and increased leukocyte infiltration, which are processes that are orchestrated by all cell types of the NVU. Their individual role in neuroinflammation is discussed below.

The liver X receptor; the missing link?

Interestingly, apart from neuroinflammation, a dysregulation of brain cholesterol homeostasis has been observed in the above-described pathological conditions. Cholesterol is a major component of cell membranes and as such it contributes to the regulation of cellular structure and function. While the brain on average only comprises 2.5% of the total body mass, it contains about 23% of the body's total cholesterol, underlining its importance in brain function (Martin et al., 2014). Almost all

Future perspectives

Activation of LXRs may be considered a promising therapeutic target in stroke, MS, and AD. LXR agonists decrease brain inflammation and exert protective effects of BBB function. Yet, there are some important points to consider before the administration of LXR agonists may become a novel therapeutic approach.

For instance, the specific roles of the individual LXRα and LXRβ subtypes are at present unknown and research focusing on LXR function in the brain rarely makes a distinction between the two

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by grants from the ZonMw Memorabel program (NMdW; project nr 733050105) and from the Dutch MS Research Foundation (AK; grant MS-09-358d).

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