scholarly journals BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease

2015 ◽  
Vol 36 (7) ◽  
pp. 1281-1294 ◽  
Author(s):  
Kavi Devraj ◽  
Slobodan Poznanovic ◽  
Christoph Spahn ◽  
Gerhard Schwall ◽  
Patrick N Harter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells ◽  
Primary Mouse ◽  
Β Amyloid ◽  
Bace 1

Endothelial cells of the blood–brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood–brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer’s disease, current treatment approaches include inhibitors of BACE-1 (β-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic β-amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood–brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D- dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer’s disease mouse model we show that BACE-1 is upregulated at the blood–brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood–brain barrier in β-amyloid generation and in vascular aspects of Alzheimer’s disease, particularly in the development of cerebral amyloid angiopathy.

scholarly journals Mouse Adenovirus Type 1-Induced Breakdown of the Blood-Brain Barrier

2009 ◽  
Vol 83 (18) ◽  
pp. 9398-9410 ◽  
Author(s):  
Lisa E. Gralinski ◽  
Shanna L. Ashley ◽  
Shandee D. Dixon ◽  
Katherine R. Spindler
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Adenovirus Type ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells ◽  
Primary Mouse ◽  
Infected Cells

ABSTRACT Infection with mouse adenovirus type 1 (MAV-1) results in fatal acute encephalomyelitis in susceptible mouse strains via infection of brain endothelial cells. Wild-type (wt) MAV-1 causes less brain inflammation than an early region 3 (E3) null virus in C57BL/6 mice. A mouse brain microvascular endothelial cell line infected with wt MAV-1 had higher expression of mRNAs for the proinflammatory chemokines CCL2 and CCL5 than mock- and E3 null virus-infected cells. Primary mouse brain endothelial cells infected with wt virus had elevated levels of CCL2 compared to mock- or E3 null virus-infected cells. Infection of C57BL/6 mice with wt MAV-1 or the E3 null virus caused a dose-dependent breakdown of the blood-brain barrier, primarily due to direct effects of virus infection rather than inflammation. The tight junction proteins claudin-5 and occludin showed reduced surface expression on primary mouse brain endothelial cells following infection with either wt MAV-1 or the E3 null virus. mRNAs and protein for claudin-5, occludin, and zona occludens 2 were also reduced in infected cells. MAV-1 infection caused a loss of transendothelial electrical resistance in primary mouse brain endothelial cells that was not dependent on E3 or on MAV-1-induced CCL2 expression. Taken together, these results demonstrate that MAV-1 infection caused breakdown of the blood-brain barrier accompanied by decreased surface expression of tight junction proteins. Furthermore, while the MAV-1-induced pathogenesis and inflammation were dependent on E3, MAV-1-induced breakdown of the blood-brain barrier and alteration of endothelial cell function were not dependent on E3 or CCL2.

P2-264: Oxysterols, Blood-Brain Barrier (BBB) and Alzheimer's Disease: in vitro studies on endothelial cells and pericytes

2011 ◽  
Vol 7 ◽  
pp. S396-S397
Author(s):  
Julien Saint-Pol ◽  
Elodie Vandenhaute ◽  
Marie-Christine Boucau ◽  
Lucie Dehouck ◽  
Roméo Cecchelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
In Vitro Studies ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

2015 ◽  
Vol 36 (1) ◽  
pp. 216-227 ◽  
Author(s):  
Matthew R Halliday ◽  
Sanket V Rege ◽  
Qingyi Ma ◽  
Zhen Zhao ◽  
Carol A Miller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Late Onset ◽  
Density Lipoprotein ◽  
Brain Barrier ◽  
Lipoprotein Receptor ◽  
Apolipoprotein E4 ◽  
Blood Brain

The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 ( APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD ( APOE4 > APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

Design and synthesis of novel tacrine–indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease

2021 ◽  
Author(s):  
Slavka Hamulakova ◽  
Zuzana Kudlickova ◽  
Ladislav Janovec ◽  
Roman Mezencev ◽  
Zachery J Deckner ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Acetylcholinesterase Inhibitors ◽  
Biological Evaluation ◽  
Brain Barrier ◽  
Amyloid Formation ◽  
Design And Synthesis ◽  
Blood Brain ◽  
Β Amyloid

The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine–indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood–brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood–brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.

Nontoxic amphiphilic carbon dots as promising drug nanocarriers across the blood–brain barrier and inhibitors of β-amyloid

Nanoscale ◽  
2019 ◽  
Vol 11 (46) ◽  
pp. 22387-22397 ◽  
Author(s):  
Yiqun Zhou ◽  
Piumi Y. Liyanage ◽  
Dinesh Devadoss ◽  
Linda Rebeca Rios Guevara ◽  
Ling Cheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Carbon Dots ◽  
Brain Barrier ◽  
Blood Brain ◽  
Β Amyloid ◽  
Amyloid P ◽  
Drug Nanocarriers

Unique nontoxic amphiphilic carbon dots have been developed as an excellent drug nanocarrier targeting the Alzheimer's disease by crossing the blood-brain barrier (BBB) while inhibiting the production of β-amyloid.

scholarly journals Histamine Induces Alzheimer’s Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jonathan C. Sedeyn ◽  
Hao Wu ◽  
Reilly D. Hobbs ◽  
Eli C. Levin ◽  
Robert G. Nagele ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
The United States ◽  
Model Systems ◽  
Brain Barrier ◽  
Astrocyte Activation ◽  
Blood Brain ◽  
Primary Mouse

Among the top ten causes of death in the United States, Alzheimer’s disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses—a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin—were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD.

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