Elizabeth M. Rhea

Blood-Brain Barriers in Obesity

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.

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

An increased risk for Alzheimers disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimers disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid β peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimers disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimers disease and Aβ peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimers disease.

Serum amyloid A: an ozone-induced circulating factor with potentially important functions in the lung-brain axis

Accumulating evidence suggests that O3 exposure may contribute to CNS dysfunction. Here, we posit that inflammatory and acute‐phase proteins in the circulation increase after O3 exposure and systemically convey signals of O3 exposure to the CNS. To model acute O3 exposure, female Balb/c mice were exposed to 3 ppm O3 or forced air for 2 h and were studied after 6 or 24 h. Of 23 cytokines and chemokines, only KC/CXCL1 was increased in blood 6 h after O3 exposure. The acute‐phase protein serum amyloid A (A‐SAA) was significantly increased by 24 h, whereas C‐reactive protein was unchanged. A‐SAA in blood correlated with total leukocytes, macrophages, and neutrophils in bronchoalveolar lavage from O3‐exposed mice. A‐SAA mRNA and protein were increased in the liver. We found that both isoforms of A‐SAA completely crossed the intact blood‐brain barrier, although the rate of SAA2.1 influx was approximately 5 times faster than that of SAA1.1. Finally, A‐SAA protein, but not mRNA, was increased in the CNS 24 h post‐O3 exposure. Our findings suggest that A‐SAA is functionally linked to pulmonary inflammation in our O3 exposure model and that A‐SAA could be an important systemic signal of O3 exposure to the CNS.—Erickson, M. A., Jude, J., Zhao, H., Rhea, E. M., Salameh, T. S., Jester, W., Pu, S., Harrowitz, J., Nguyen, N., Banks, W. A., Panettieri, R. A., Jr., Jordan‐Sciutto, K. L. Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis. FASEB J. 31, 3950–3965 (2017). www.fasebj.org—Erickson, Michelle A., Jude, Joseph, Zhao, Hengjiang, Rhea, Elizabeth M., Salameh, Therese S., Jester, William, Pu, Shelley, Harrowitz, Jenna, Nguyen, Ngan, Banks, William A., PanettieriJr., Reynold A., Jordan‐Sciutto, Kelly L. Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis. FASEB J. 31, 3950–3965 (2017)

Gut reactions: How the blood–brain barrier connects the microbiome and the brain:

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.

Intranasal Insulin Transport is Preserved in Aged SAMP8 Mice and is Altered by Albumin and Insulin Receptor Inhibition

Insulin delivered to the level of the cribriform plate (intranasal insulin) is being investigated for its ability to enhance memory in people with Alzheimers disease (AD). Recent work has shown intranasal insulin can be detected in young CD-1 mice within 5 min and is still present 60 min after injection. The current study determined whether intranasal insulin transport and the subsequent brain distribution of insulin varies in young, healthy mice (CD-1) compared to those with an AD-like phenotype (aged SAMP8) or those pre-disposed to develop such a phenotype (young SAMP8). We showed transport does not vary among these three mouse cohorts, suggesting that intranasal uptake and brain pharmacokinetics do not differ with AD-like signs or the genetic predisposition to developing them. We found that co-administration with bovine serum albumin increased levels of insulin in most brain regions. In addition, the insulin receptor inhibitor, S961, decreases the amount of insulin transported throughout the brain after intranasal injection. These results show insulin delivery to the brain by intranasal administration can be modified with agents such as albumin, may be dependent on the insulin receptor, and is not affected by an AD-like phenotype as presented by the SAMP8 mouse.

The SAMP8 mouse for investigating memory and the role of insulin in the brain.

&NA; SAMP8 mice exhibit changes that commonly occur with normal aging late in life, but do so at a much earlier age. These changes include impairments in learning and memory as early as 8 months of age and so the SAMP8 is a useful model to investigate those age‐related brain changes that may affect cognition. As brain insulin signaling and memory decline with aging, the SAMP8 model is useful for investigating these changes and interventions that might prevent the decline. This review will summarize the SAMP8 mouse model, highlight changes in brain insulin signaling and its role in memory, and discuss intranasal insulin delivery in investigating effects on insulin metabolism and memory in the SAMP8 mice. HighlightsSAMP8 mice are a useful model for investigating memory changes due to aging.SAMP8 mice are a useful model for investigating changes in brain insulin signaling.SAMP8 mice could be useful for investigating effects of intranasal insulin.

Insulin transport across the blood–brain barrier can occur independently of the insulin receptor

Insulin enters the brain from the blood via a saturable transport system. It is unclear how insulin is transported across the blood–brain barrier (BBB). Using two models of the signalling‐related insulin receptor loss or inhibition, we show insulin transport can occur in vivo without the signalling‐related insulin receptor. Insulin in the brain has multiple roles including acting as a metabolic regulator and improving memory. Understanding how insulin is transported across the BBB will aid in developing therapeutics to further increase CNS concentrations.

Effect of controlled cortical impact on the passage of pituitary adenylate cyclase activating polypeptide (PACAP) across the blood-brain barrier

HighlightsPACAP38 transport across the BBB is not dramatically altered following CCI.The ipsilateral cortex has increased PACAP38 levels 2 h and 24 h following CCI.There is no change in the rate of PACAP38 transport at these times.The cerebellum contains the greatest amount and fastest rate of PACAP38 transport. ABSTRACT Injuries to the central nervous system can affect the blood‐brain barrier (BBB), including disruption and influencing peptide transport across the BBB. Pituitary adenylate cyclase‐activating polypeptide 38 (PACAP38) is a potent neurotrophic and neuroprotective peptide currently being investigated for its therapeutic role following injury to the central nervous system and can cross the BBB in a saturable manner. The goal of the current study was to investigate for the first time PACAP38 uptake by the brain following traumatic brain injury (TBI). Using radioactively labeled PACAP38, we measured the levels of PACAP38 present in the injured, ipsilateral cortex in Sham‐treated mice compared to mice receiving a controlled cortical impact (CCI), a model of TBI. Experiments were conducted at 6 different time points (from 2 h up to 4 weeks) following CCI to determine temporal changes in PACAP38 transport. PACAP38 uptake was increased at 2 and 72 h post‐CCI compared to Sham. We did not detect changes in PACAP38 uptake in the contralateral cortex and cerebellum between Sham and CCI‐treatment. The rate of PACAP38 transport into the ipsilateral cortex following CCI was increased 3.6‐fold 72 h after compared to 2 h post‐CCI. In addition, the rate of transport into the cerebellum was greater than that of the cortices. The data presented here shows PACAP38 transport is temporally altered following CCI‐treatment and PACAP38 uptake is greater in the cerebellum compared to the cortices.

Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor

Objective The blood–brain barrier (BBB) regulates the entry of substrates and peptides into the brain. Ghrelin is mainly produced in the stomach but exerts its actions in the central nervous system (CNS) by crossing the BBB. Once present in the CNS, ghrelin can act in the hypothalamus to regulate food intake, in the hippocampus to regulate neurogenesis, and in the olfactory bulb to regulate food-seeking behavior. The goal of this study was to determine whether the primary signaling receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), mediates the transport of ghrelin from blood to brain. Methods We utilized the sensitive and quantitative multiple-time regression analysis technique to determine the transport rate of mouse and human acyl ghrelin (AG) and desacyl ghrelin (DAG) in wildtype and Ghsr null mice. We also measured the regional distribution of these ghrelin peptides throughout the brain. Lastly, we characterized the transport characteristics of human DAG by measuring the stability in serum and brain, saturability of transport, and the complete transfer across the brain endothelial cell. Results We found the transport rate across the BBB of both forms of ghrelin, AG, and DAG, were not affected by the loss of GHSR. We did find differences in the transport rate between the two isoforms, with DAG being faster than AG; this was dependent on the species of ghrelin, human being faster than mouse. Lastly, based on the ubiquitous properties of ghrelin throughout the CNS, we looked at regional distribution of ghrelin uptake and found the highest levels of uptake in the olfactory bulb. Conclusions The data presented here suggest that ghrelin transport can occur independently of the GHSR, and ghrelin uptake varies regionally throughout the brain. These findings better our understanding of the gut-brain communication and may lead to new understandings of ghrelin physiology.