It is unclear whether SARS-CoV-2, which causes COVID-19, can enter the brain. SARS-CoV-2 binds to cells via the S1 subunit of its spike protein. We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood-brain barrier (BBB) in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by lung, spleen, kidney, and liver. Intranasally administered I-S1 also entered the brain, though at ~10 times lower levels than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake, but had variable effects on uptake by the olfactory bulb, liver, spleen, and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the BBB by adsorptive transcytosis, and that murine angiotensin-converting enzyme-2 is involved in brain and lung uptake, but not in kidney, liver, or spleen uptake.

The blood-brain barrier (BBB) mediates the communication between the periphery and the central nervous system (CNS). Recently, CNS insulin resistance has been elucidated to play a role in neurodegenerative disease. This has stimulated a wealth of information on the molecular impact of insulin in the brain, particularly in the improvement of cognition. Since the BBB regulates the transport of insulin into the brain and thus, helps to regulate CNS levels, alterations in the BBB response to insulin could impact CNS insulin resistance. In this review, we summarize the effect of insulin on some of the cell types that make up the BBB, including endothelial cells, neurons, astrocytes, and pericytes. We broadly discuss how these changes in specific cell types could ultimately impact the BBB. We also summarize how insulin can regulate levels of the pathological hallmarks of Alzheimer’s disease, including amyloid beta (Aβ) and tau within each cell type. Finally, we suggest interventional approaches to overcome detrimental effects on the BBB in regards to changes in insulin transport.

A growing body of evidence indicates that the microbiome interacts with the central nervous system (CNS) and can regulate many of its functions. One mechanism for this interaction is at the level of the blood-brain barriers (BBBs). In this minireview, we examine the several ways the microbiome is known to interact with the CNS barriers. Bacteria can directly release factors into the systemic circulation or can translocate into blood. Once in the blood, the microbiome and its factors can alter peripheral immune cells to promote interactions with the BBB and ultimately with other elements of the neurovascular unit. Bacteria and their factors or cytokines and other immune-active substances released from peripheral sites under the influence of the microbiome can cross the BBB, alter BBB integrity, change BBB transport rates, or induce release of neuroimmune substances from the barrier cells. Metabolic products produced by the microbiome, such as short-chain fatty acids, can cross the BBB to affect brain function. Through these and other mechanisms, microbiome-BBB interactions can influence the course of diseases as illustrated by multiple sclerosis. Impact statement The connection between the gut microbiome and central nervous system (CNS) disease is not fully understood. Host immune systems are influenced by changes to the microbiota and offers new treatment strategies for CNS disease. Preclinical studies provide evidence of changes to the blood-brain barrier when animals are subject to experimental gut infection or when the animals lack a normal gut microbiome. The intestine also contains a barrier, and bacterial factors can translocate to the blood and interact with host immune cells. These metastatic bacterial factors can signal T-cells to become more CNS penetrant, thus providing a novel intervention for treating CNS disease. Studies in humans show the therapeutic effects of T-cell engineering for the treatment of leukemia, so perhaps a similar approach for CNS disease could prove effective. Future research should begin to define the bacterial species that can cause immune cells to differentiate and how these interactions vary amongst CNS disease models.

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.

Objective:Resistance at the brain receptors for leptin and insulin has been associated with increased feeding, obesity and cognitive impairments. The causal agent for central resistance is unknown but could be derived from the blood. Here we postulate whether hypertriglyceridemia, the major dyslipidemia of the metabolic syndrome, could underlie central leptin and insulin resistance.Design:We used radioactively labeled triglycerides to measure blood–brain barrier (BBB) penetration, western blots to measure receptor activation, and feeding and cognitive tests to assess behavioral endpoints.Results:Human CSF was determined to contain triglycerides, a finding previously unclear. The radioactive triglyceride triolein readily crossed the BBB and centrally administered triolein and peripherally administered lipids induced in vivo leptin and/or insulin resistance at hypothalamic receptors. Central triolein blocked the satiety effect of centrally administered leptin. Decreasing serum triglycerides with gemfibrozil improved both learning and memory inversely proportionate to triglyceride levels.Conclusions:Triglycerides cross the blood–brain barrier rapidly, are found in human cerebrospinal fluid, and induce central leptin and insulin receptor resistance, decreasing satiety and cognition.

The blood-brain barrier (BBB) protects the central nervous system (CNS) from unregulated exposure to the blood and its contents. The BBB also controls the blood-to-brain and brain-to-blood permeation of many substances, resulting in nourishment of the CNS, its homeostatic regulation and communication between the CNS and peripheral tissues. The cells forming the BBB communicate with cells of the brain and in the periphery. This highly regulated interface changes with healthy aging. Here, we review those changes, starting with morphology and disruption. Transporter changes include those for amyloid beta peptide, glucose and drugs. Brain fluid dynamics, pericyte health and basement membrane and glycocalyx compositions are all altered with healthy aging. Carrying the ApoE4 allele leads to an acceleration of most of the BBB's age-related changes. We discuss how alterations in the BBB that occur with healthy aging reflect adaptation to the postreproductive phase of life and may affect vulnerability to age-associated diseases.

A saturable system transports insulin from blood across the blood-brain barrier (BBB) and into the central nervous system. Whether or not the classic or signalling-related insulin receptor plays a role in mediating this transport in vivo is controversial. Here, we employed kinetics methods that distinguish between transport across the brain endothelial cell and reversible luminal surface receptor binding. Using a previously established line of mice with endothelial-specific loss of the signalling-related insulin receptor (EndoIRKO) or inhibiting the insulin receptor with the selective antagonist S961, we show insulin transport across the BBB is maintained. Rates of insulin transport were similar in all groups and transport was still saturable. Unlike transport, binding of insulin to the brain endothelial cell was decreased with the loss or inhibition of the signalling-related insulin receptor. These findings demonstrate that the signalling-related insulin receptor is not required for insulin transport across the BBB.

After decades of rapid increase, the rate of obesity in adults in the USA is beginning to slow and the rate of childhood obesity is stabilizing. Despite these improvements, the obesity epidemic continues to be a major health and financial burden. Obesity is associated with serious negative health outcomes such as cardiovascular disease, type II diabetes, and, more recently, cognitive decline and various neurodegenerative dementias such as Alzheimer’s disease. In the past decade, major advancements have contributed to the understanding of the role of the central nervous system (CNS) in the development of obesity and how peripheral hormonal signals modulate CNS regulation of energy homeostasis. In this article, we address how obesity affects the structure and function of the blood-brain barrier (BBB), the impact of obesity on Alzheimer’s disease, the effects of obesity on circulating proteins and their transport into the brain, and how these changes can potentially be reversed by weight loss.