Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

The role of interleukin 6 on blood-brain barrier permeability and structure in secondary brain injury after subarachnoid hemorrhage

Der Zusammenbruch der Blut-Hirn-Schranke (BHS) spielt eine bedeutende Rolle beim Verständnis der sekundären Hirnschädigung nach Subarachnoidalblutung (SAB). Im proinflammatorischen Milieu nach SAB wird Interleukin (IL) 6 ein entscheidender Effekt auf das zerebrovaskuläre Leakage und die Bestandteile der Neurovaskulären Unit (NVU) zugeschrieben. Diese Arbeit charakterisiert neben Ausmaß und Ursachen der BHS-Schädigung den Einfluss des IL6 auf die BHS-Integrität in einem SAB-Mausmodell. Die SAB wurde in Wildtyp (WT) und IL6 Knock Out (KO) Mäusen mittels Filament-Perforations-Methode induziert. SAB und scheinoperierte SHAM-Tiere (Kontrollen) wurden an Tag 4 nach stattgehabter Blutung getötet. Die BHS-Permeabilität wurde anhand der Extravasation fluoreszierender Tracer, Evans Blue (EB, 70 kDa) und Fluorescein Isothiocyanate- (FITC)-Dextran (FD, 4 kDa), eruiert. Der Hirnwassergehalt wurde über das Verhältnis des Nass- zu Trockengewichts ermittelt. Die endotheliale Expression von Tight Junctions (TJ), Zytokinen (IL6, IL1β und Tumornekrosefaktor (TNF) α) und der Matrix-Metalloproteinase 9 (MMP9) wurde in isolierten Hirnkapillaren via qPCR untersucht. Die Verteilung von Collagen IV sowie apoptotische Desmin- und TUNEL-positive Perizyten wurden per Immunfluoreszenzmikroskopie ermittelt. An Tag 4 nach SAB wurde eine signifikante IL6-Überexpression (2,7 ± 0,5-fach) in WT beobachtet. Während FD in beiden Gruppen (WT und IL6 KO) in das Parenchym extravasierte, konnte eine SAB-induzierte EB-Extravasation lediglich bei WT beobachtet werden. Der Hirnwassergehalt lag bei WT nach SAB signifikant um 2,66 ± 0,47 % höher als bei IL6 KOs. Eine signifikante Rekonstitution der Occludin- (1,79 ± 0,14-fach der Expression der SHAM-Tiere), jedoch nicht der Claudin-5-Expression (0,86 ± 0,56-fach) konnte in SAB-operierten IL6 KO-Mäusen im Vergleich zu WT-Mäusen beobachtet werden. Außerdem konnte eine Hochregulation von IL1β und TNFα in WT nach SAB festgestellt werden (je 2,3 ± 0,99-fach und 2,18 ± 0,77-fach der SHAM-Kontrollgruppe), wohingegen in IL6 KOs eine geringere Expression bestimmt wurde. Abschließend wurde eine höhere Anzahl apoptotischer Perizyten in SAB WT-Tieren im Vergleich mit der IL6 KO-Gruppe detektiert. Der Verlust der BHS-Integrität in WT-Mäusen nach SAB konnte anhand der EB-Extravasation sowie der verringerten TJ-Expression demonstriert werden. Die unterbundene EB-Passage, die partiell wiederhergestellte TJ-Expression und die weniger starke Beanspruchung von extrazellulärer Matrix sowie Endothel-Perizyten-Interaktion in IL6 KOs sind Indikatoren dafür, dass die BHS-Dichtigkeit in diesen Mäusen nach SAB besser erhalten wird. Der Einfluss des IL6 auf das zerebrovaskuläre Leakage sowie sein Effekt auf die NVU machen die zentrale Rolle dieses Zytokins bei der sekundären Hirnschädigung nach SAB deutlich.Studying disruption of the blood-brain barrier (BBB) is central for the understanding of secondary brain injury after subarachnoid hemorrhage (SAH). Interleukin (IL) 6 has been postulated to affect cerebrovascular leakage and neurovascular unit components (NVU) under proinflammatory conditions following SAH. The presented work focuses on investigating the extent and causes of BBB breakdown, along with the influence of IL6 on BBB integrity in a SAH mouse model. Methods: Filament perforation model was used to induce SAH in wildtype (WT) and IL6 knock out (KO) mice. SAH- and SHAM-operated animals (controls) were sacrificed 4 days after the onset of the bleeding. By extravasation of fluorescents Evans Blue (EB, 70 kDa) and Fluorescein Isothiocyanate- (FITC)-Dextran (FD, 4 kDa) BBB permeability was assessed. Brain water content was determined applying the wet/dry weight method. Endothelial expressions of tight junctions (TJ), cytokines (IL6, IL1β, tumor-necrosis factor (TNF) α and matrix metalloproteinase 9 (MMP9) were analyzed in isolated brain capillaries by applying qPCR. Apoptotic desmin- and TUNEL-double-positive pericytes and the distribution of Collagen IV were assessed by conducting immunofluorescence microscopy. Results: On day 4 post-SAH, a significant IL6 overexpression (2.7 ± 0.5-fold) was detected in WTs. While FD extravasated in both groups, SAH-induced EB-extravasation was noticed only in WT mice. In comparison to IL6KOs, WT mice showed significantly higher brain water content after SAH (2.66 % ± 0.47 %). A significant reconstitution of occludin (1.79 ± 0.14-fold of SHAM) but not claudin-5 (0.86 ± 0.56-fold) was detected in SAHoperated IL6KOs compared to WTs. This study revealed IL1β and TNFα to be upregulated in WTs post SAH (2.3 ± 0.99-fold and 2.18 ± 0.77-fold of SHAM). This overexpression was attenuated in IL6KOs. Finally, degradation of extracellular matrix (ECM) and significantly more apoptotic pericytes were detected in SAH-WTs (3.1 ± 1.0- fold) compared to IL6KOs. Conclusion: The loss of BBB integrity in WT mice post SAH in terms of EB extravasation and lower TJ expression was demonstrated. Considering the constriction of EB extravasation, the partial reconstitution of TJ expression and the lower affection of ECM and endothelialpericyte interaction, we deduce that BBB tightness could be obtained more effectively in IL6KOs. Due to its proinflammatory influence on cerebrovascular leakage and its effect on NVU-components, we infer that IL6 is decisively involved in the presence of secondary brain injury post SAH

Link between Insomnia and the Development of Alzheimer\u27s disease?

Alzheimer’s disease (AD) is the most common type of dementia, affecting many adults over the age of 65. There is no known cure of AD. According to the Alzheimer’s Association, “every 65 seconds, someone in the United States develops Alzheimer’s disease” (2019). “Alzheimer’s causes problems with memory, thinking and behavior. Symptoms develop slowly and can become severe enough to interfere with daily tasks. Alzheimer’s disease is the sixth leading cause of death in the United States, with an estimated 5.7 million Americans of all ages are living with AD in 2018 (Alzheimer’s Association, 2019). The recommended amount of sleep per night for older adults is 7-8 hours (National Sleep Foundation, 2019). Insomnia is a common sleep disorder, with symptoms of difficulty falling asleep, staying asleep, or both, as stated by the National Institutes of Health (2019). Forty-four percent of people over the age of 65 experience symptoms of insomnia. It is suggested that insomnia increases the development of one of the major pathological agents in AD: amyloid-beta plaques. The purpose of this Evidenced Based Practice Brief is to research how insomnia compared to adequate sleep in patients sixty-five years and older increases the risk of the development of AD. By looking at the research regarding whether insomnia increases a patient’s risk of developing Alzheimer’s disease, nurses will be able to provide current evidence based practice when aiding in preventative strategies for Alzheimer’s disease

J Gerontol B Psychol Sci Soc Sci

Objectives: Several epidemiological studies suggest declining trends in dementia over the last three decades with both decreasing age-specific prevalence and incidence. There is limited data on whether this delayed clinical onset is accompanied by a shorter postdiagnosis survival. Methods: A total of 5,205 participants from the Framingham Original and Offspring cohorts were studied. Four epochs were considered from 1977-1984 to 2004-2008. Gender and education adjusted 5-year mortality risks were estimated using delayed entry Cox models with the earliest epoch as reference category. Stratified analyses by sex, education, and age were undertaken. A nested case control study of 317 dementia cases and 317 controls matched on age, gender and epoch was initiated. Results: In the whole sample, 5-year mortality risk has decreased with time, it was 33% lower in the last epoch compared to the earliest. In the 317 persons who developed dementia, age at onset increased (1.5 years/epoch), and years alive with dementia decreased (1 year/epoch) over time. We observed however, a decreased adjusted relative mortality risk (by 18%) in persons with dementia in 1986-1991 compared to 1977-1983 and no significant change from then to the latest epoch. The nested case control study suggested in matched controls that 5-year mortality relative risk had increased by 60% in the last epoch compared to Epoch 1. Discussion: In the FHS, in the last 30 years, disease duration in persons with dementia has decreased. However, age-adjusted mortality risk has slightly decreased after 1977-1983. Consequences of such trends on dementia prevalence should be investigated