Extracellular vesicles through the blood-brain barrier: a review.

Extracellular vesicles (EVs) are particles naturally released from cells that are delimited by a lipid bilayer and are unable to replicate. How the EVs cross the Blood-Brain barrier (BBB) in a bidirectional manner between the bloodstream and brain parenchyma remains poorly understood. Most in vitro models that have evaluated this event have relied on monolayer transwell or microfluidic organ-on-a-chip techniques that do not account for the combined effect of all cellular layers that constitute the BBB at different sites of the Central Nervous System. There has not been direct transcytosis visualization through the BBB in mammals in vivo, and evidence comes from in vivo experiments in zebrafish. Literature is scarce on this topic, and techniques describing the mechanisms of EVs motion through the BBB are inconsistent. This review will focus on in vitro and in vivo methodologies used to evaluate EVs transcytosis, how EVs overcome this fundamental structure, and discuss potential methodological approaches for future analyses to clarify these issues. Understanding how EVs cross the BBB will be essential for their future use as vehicles in pharmacology and therapeutics.

Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-ß (Aß) peptide. We have previously shown that the compound tetrahydrohyperforin (IDN5706) prevents accumulation of Aß species in an in vivo model of AD, however the mechanism that explains this reduction is not well understood. We show herein that IDN5706 decreases the levels of ER degradation enhancer, mannosidase alpha-like 1 (EDEM1), a key chaperone related to endoplasmic-reticulum-associated degradation (ERAD). Moreover, we observed that low levels of EDEM1 correlated with a strong activation of autophagy, suggesting a crosstalk between these two pathways. We observed that IDN5706 perturbs the glycosylation and proteolytic processing of the amyloid precursor protein (APP), resulting in the accumulation of immature APP (iAPP) in the endoplasmic reticulum. To investigate the contribution of autophagy, we tested the effect of IDN5706 in Atg5-depleted cells. We found that depletion of Atg5 enhanced the accumulation of iAPP in response to IDN5706 by slowing down its degradation. Our findings reveal that IDN5706 promotes degradation of iAPP via the activation of Atg5-dependent autophagy, shedding light on the mechanism that may contribute to the reduction of Aß production in vivo.

Production of a type 2 maternal diabetes rodent model using the combination of high-fat diet and moderate dose of streptozocin.

INTRODUCTION: Pregnancy may be complicated by maternal diabetes. The following experiments were performed in an attempt to produce mouse models of insulin-resistant maternal diabetes. METHODS: CD1 females received 200 mg/kg streptozocin (STZ) to model insulin-dependent diabetes (T1 group). Another group of females (T2 group) was put on a HFD 4 weeks before receiving 100 mg/kg STZ. After 4 additional weeks of HFD, hyperglycemic females were separated and bred. In another experiement, CD1 females were fed a HFD for 4 weeks before receiving an intravenous (GDM1 group) or intraperitoneal (GDM2 group) injection of 100 mg/kg STZ. Females from GDM2 group were bred at the same day of the STZ injection. Females from GDM1 group were bred 4 weeks after the STZ injection. RESULTS AND CONCLUSION: About 25% of the females from T2 group became hyperglycemic after 4 weeks of the injection of STZ. Fifty percent of the females from GDM1 group reached hyperglycemic levels greater than 250 mg/dl during pregnancy. The combination of HFD and moderate STZ in CD1 mice therefore produced hyperglycemic females; however numbers of these mice were somewhat low.