scholarly journals Oligomeric Amyloid-β Peptide on Sialylic Lewisx–Selectin Bonding at Cerebral Endothelial Surface

2014 ◽  
Vol 3 ◽  
Author(s):  
Sholpan Askarova ◽  
Grace Y. Sun ◽  
Gerald A. Meininger ◽  
James Lee
Keyword(s):  
Endothelial Cells ◽  
Actin Polymerization ◽  
Neurodegenerative Disorder ◽  
Practical Importance ◽  
Amyloid Β ◽  
Cell Stiffness ◽  
Amyloid Β Peptide ◽  
Rupture Force ◽  
Adhesion Properties ◽  
Cerebral Endothelial Cells

Introduction: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder, which affects approximately 10% of the population aged 65 and 40% of people over the age 80. Currently, AD is on the list of diseases with no effective treatment. Thus, the study of molecular and cellular mechanisms of AD progression is of high scientific and practical importance. In fact, dysfunction of the blood-brain barrier (BBB) plays an important role in the onset and progression of the disease. Increased deposition of amyloid b peptide (Aβ) in cerebral vasculature and enhanced transmigration of monocytes across the BBB are frequently observed in AD brains and are some of the pathological hallmarks of the diseases. Since the transmigration of monocytes across the BBB is both a mechanical and a biochemical process, the expression of adhesion molecules and mechanical properties of endothelial cells are the critical factors that require investigation.Methods: Because of recent advances in the biological applications of atomic force microscopy (AFM), we applied AFM with cantilever tips bio-functionalized by sLex in combination with the advanced immunofluorescent microscopy (QIM) to study the direct effects of Aβ42 oligomers on the selectins expression, actin polymerization, and cellular mechanical and adhesion properties in cerebral endothelial cells (mouse bEnd3 line and primary human CECs) and find a possible way to attenuate these effects. Results: QIM results showed that Aβ42 increased the expressions of P-selectin on the cell surface and enhanced actin polymerization. Consistent with our QIM results, AFM data showed that Aβ42 increased the probability of cell adhesion with sLex-coated cantilever and cell stiffness. These effects were counteracted by lovstatin, a cholesterol-lowering drug.  Surprisingly, the apparent rupture force of sLex-selectin bonding was significantly lower after treatment with Aβ42, as compared with the control (i.e. no treatment). Similar results were also obtained when cells were treated with latruculin A (F-actin-disrupting drug). These results suggest that the decrease in the apparent rupture force of sLex-selectin bonding is the consequence of the dissociation of adhesion between the cytoskeleton and the bilayer membrane induced by Aβ42. The major causes of excess mortality in the first group were neoplams (30.6%), hypertension (23.8%), and myocardial infarction (22.6%). The effects of radiation influenced mortality in the second group were 2-2.5 times lower than the first group. Conclusion: The studies of the effects of Aβ42 on the adhesion properties of cerebral endothelial cells and how pharmacological agents (e.g. statin) counteract these effects should prove to provide insights into the mechanism of inflammation in Alzheimer’s brains and the design of therapeutic treatments of the disease.

scholarly journals Tip60 protects against amyloid-β peptide-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegenerative progression

2020 ◽  
Author(s):  
Haolin Zhang ◽  
Bhanu Chandra Karisetty ◽  
Akanksha Bhatnagar ◽  
Ellen M. Armour ◽  
Mariah Beaver ◽  
...  
Keyword(s):  
Cell Death ◽  
Cognitive Deficits ◽  
Late Stage ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Peptide ◽  
Histone Deacetylase 2 ◽  
Age Related ◽  
Late Stages

ABSTRACTAlzheimer’s disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-β42. We show that early Aβ42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the Aβ42 fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.

Hypoxia alters biophysical properties of endothelial cells via p38 MAPK- and Rho kinase-dependent pathways

2005 ◽  
Vol 289 (3) ◽  
pp. C521-C530 ◽  
Author(s):  
Steven S. An ◽  
Corin M. Pennella ◽  
Achuta Gonnabathula ◽  
Jianxin Chen ◽  
Ning Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Actin Polymerization ◽  
Rho Kinase ◽  
Small Heat Shock Protein ◽  
Cell Stiffness ◽  
Microvascular Endothelial Cells ◽  
Pulmonary Vasculature ◽  
Biophysical Properties ◽  
Traction Forces ◽  
Downstream Effector

Hypoxia alters the barrier function of the endothelial cells that line the pulmonary vasculature, but underlying biophysical mechanisms remain unclear. Using rat pulmonary microvascular endothelial cells (RPMEC) in culture, we report herein changes in biophysical properties, both in space and in time, that occur in response to hypoxia. We address also the molecular basis of these changes. At the level of the single cell, we measured cell stiffness, the distribution of traction forces exerted by the cell on its substrate, and spontaneous nanoscale motions of microbeads tightly bound to the cytoskeleton (CSK). Hypoxia increased cell stiffness and traction forces by a mechanism that was dependent on the activation of Rho kinase. These changes were followed by p38-mediated decreases in spontaneous bead motions, indicating stabilization of local cellular-extracellular matrix (ECM) tethering interactions. Cells overexpressing phospho-mimicking small heat shock protein (HSP27-PM), a downstream effector of p38, exhibited decreases in spontaneous bead motions that correlated with increases in actin polymerization in these cells. Together, these findings suggest that hypoxia differentially regulates endothelial cell contraction and cellular-ECM adhesion.

Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

2011 ◽  
Vol 39 (3) ◽  
pp. 819-822 ◽  
Author(s):  
Ana M. Mata ◽  
María Berrocal ◽  
M. Rosario Sepúlveda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

Abstract WMP82: Exosomes Derived From Cerebral Endothelial Cells of Young Adult Rats Reduced Cognitive Deficits in Aged Diabetic Rats

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Li Zhang ◽  
Michael Chopp ◽  
Chao Li ◽  
Quan Jiang ◽  
Guang Liang Ding ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cognitive Function ◽  
Young Adult ◽  
Cognitive Decline ◽  
Brain Slices ◽  
Amyloid Β ◽  
Adult Rats ◽  
Glymphatic System ◽  
Cerebral Endothelial Cells

Introduction: Diabetes mellitus (DM) is associated with cognitive decline and dementia in the elderly. The glymphatic system mediates clearance of the interstitial solutes in the brain by exchange of cerebrospinal and interstitial fluid (CSF and ISF). We recently demonstrated that DM in aged rat induces impairment of the glymphatic system and cognitive decline. Exosomes, membrane vesicles, mediate intercellular communication by transferring their cargo into recipient cells. The present study investigated whether cerebral endothelial exosomes (CEE) ameliorate glymphatic system impairment and improve cognitive function in aged DM rats. Methods and Results: DM was induced in male Wistar rats (13 months, n=48) by injection of nicotinamide and streptozotocin. Two months after DM, rats were treated with CEE (1x10 11 exosomes/rat, IV) twice a week for 4 weeks. Age matched DM and non-DM rats were used as controls. CEE were harvested from the cultured cerebral endothelial cells of health young adult rats. Exchanges of CSF and ISF were measured by intracisternal injection of fluorescent tracer, Texas Red-dextran (TR, 3kD). Confocal microscopic analysis of brain slices revealed a progressive slowdown of ISF clearance in the hippocampi, assessed by retention of TR starting at 2.5 fold at 2M (13±5 vs 5±3% of area) and increasing to 4 fold at 4M (21±4 vs 5±2%) of DM. Paravascular amyloid β (Aβ) accumulation was only detected at 4M of DM. The CEE treatment significantly (p<0.05) reduced TR retention (10±4%) at 4M of DM and also decreased Aβ accumulation (2±1 vs 6±2/mm 2 ) and parenchymal fibrin deposition (9±5 vs 23±5/mm 2 ) compared to untreated DM rats. Moreover, the CEE treatment significantly improved hippocampal related learning and memory measured by the Morris Water Maze and odor-based novelty recognition for olfactory memory, without altering the glucose level. In vitro, cerebral endothelial cells isolated from 2M DM rats exhibited substantial dysfunction as measured by capillary-like tube formation and cell migration, whereas incubation with the CEE substantially reversed endothelial dysfunction. Conclusions: The CEE treatment reduces DM-induced glymphatic and cerebral endothelial dysfunctions, leading to improvement of cognitive function in aged DM rats.

scholarly journals Oxidative Stress Boosts the Uptake of Cerium Oxide Nanoparticles by Changing Brain Endothelium Microvilli Pattern

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 266
Author(s):  
Roberta Dal Magro ◽  
Agostina Vitali ◽  
Stefano Fagioli ◽  
Alberto Casu ◽  
Andrea Falqui ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Cerium Oxide ◽  
Amyloid Β ◽  
Cerium Oxide Nanoparticles ◽  
Antioxidant Compounds ◽  
Oxide Nanoparticles ◽  
Amyloid Β Peptide ◽  
Potent Inducer ◽  
Therapeutic Benefits

Vascular oxidative stress is considered a worsening factor in the progression of Alzheimer’s disease (AD). Increased reactive oxygen species (ROS) levels promote the accumulation of amyloid-β peptide (Aβ), one of the main hallmarks of AD. In turn, Aβ is a potent inducer of oxidative stress. In early stages of AD, the concomitant action of oxidative stress and Aβ on brain capillary endothelial cells was observed to compromise the blood–brain barrier functionality. In this context, antioxidant compounds might provide therapeutic benefits. To this aim, we investigated the antioxidant activity of cerium oxide nanoparticles (CNP) in human cerebral microvascular endothelial cells (hCMEC/D3) exposed to Aβ oligomers. Treatment with CNP (13.9 ± 0.7 nm in diameter) restored basal ROS levels in hCMEC/D3 cells, both after acute or prolonged exposure to Aβ. Moreover, we found that the extent of CNP uptake by hCMEC/D3 was +43% higher in the presence of Aβ. Scanning electron microscopy and western blot analysis suggested that changes in microvilli structures on the cell surface, under pro-oxidant stimuli (Aβ or H2O2), might be involved in the enhancement of CNP uptake. This finding opens the possibility to exploit the modulation of endothelial microvilli pattern to improve the uptake of anti-oxidant particles designed to counteract ROS-mediated cerebrovascular dysfunctions.

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