Role of membrane biophysics in Alzheimer's-related cell pathways.

Cellular membrane alterations are commonly observed in many diseases, including Alzheimer's disease (AD). Membrane biophysical properties, such as membrane molecular order, membrane fluidity, organization of lipid rafts, and adhesion between membrane and cytoskeleton, play an important role in various cellular activities and functions. While membrane biophysics impacts a broad range of cellular pathways, this review addresses the role of membrane biophysics in amyloid-β peptide aggregation, Aβ-induced oxidative pathways, amyloid precursor protein processing, and cerebral endothelial functions in AD.

Role of cytosolic phospholipase A2 in oxidative and inflammatory signaling pathways in different cell types in the central nervous system.

Phospholipases A(2) (PLA(2)s) are important enzymes for the metabolism of fatty acids in membrane phospholipids. Among the three major classes of PLA(2)s in the mammalian system, the group IV calcium-dependent cytosolic PLA(2) alpha (cPLA(2)α) has received the most attention because it is widely expressed in nearly all mammalian cells and its active participation in cell metabolism. Besides Ca(2+) binding to its C2 domain, this enzyme can undergo a number of cell-specific post-translational modifications, including phosphorylation by protein kinases, S-nitrosylation through interaction with nitric oxide (NO), as well as interaction with other proteins and lipid molecules.

Cellular membrane fluidity in amyloid precursor protein processing.

The senile plaque is a pathologic hallmark of Alzheimer's disease (AD). Amyloid-β peptide (Aβ), the main constituent of senile plaques, is neurotoxic especially in its oligomeric form. Aβ is derived from the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases in the amyloidogenic pathway.

Nanoparticle-emitted light attenuates amyloid-β-induced superoxide and inflammation in astrocytes.

Unlabelled: Alzheimer's disease (AD) is the sixth leading cause of age-related death with no effective intervention yet available. Our previous studies have demonstrated the potential efficacy of Low Level Laser Therapy (LLLT) in AD cell models by mitigating amyloid-β peptide (Aβ)-induced oxidative stress and inflammation. However, the penetration depth of light is still the major challenge for implementing LLLT in animal models and in the clinical settings.

Amyloid-β peptide on sialyl-Lewis(X)-selectin-mediated membrane tether mechanics at the cerebral endothelial cell surface.

Increased deposition of amyloid-β peptide (Aβ) at the cerebral endothelial cell (CEC) surface has been implicated in enhancement of transmigration of monocytes across the brain blood barrier (BBB) in Alzheimer's disease (AD). In this study, quantitative immunofluorescence microscopy (QIM) and atomic force microscopy (AFM) with cantilevers biofunctionalized by sialyl-Lewis(x) (sLe(x)) were employed to investigate Aβ-altered mechanics of membrane tethers formed by bonding between sLe(x) and p-selectin at the CEC surface, the initial mechanical step governing the transmigration of monocytes. QIM results indicated the ability for Aβ to increase p-selectin expression at the cell surface and promote actin polymerization in both bEND3 cells (immortalized mouse CECs) and human primary CECs.

Effects of Amyloid Beta Peptide on Neurovascular Cells.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder, which is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in specific regions of the brain, accompanied by impairment of the neurons, and progressive deterioration of cognition and memory of affected individuals. Although the cause and progression of AD are still not well understood, the amyloid hypothesis is dominant and widely accepted. According to this hypothesis, an increased deposition of amyloid-β peptide (Aβ) in the brain is the main cause of the AD's onset and progression.

Impacts of membrane biophysics in Alzheimer's disease: from amyloid precursor protein processing to aβ Peptide-induced membrane changes.

An increasing amount of evidence supports the notion that cytotoxic effects of amyloid-β peptide (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD), are strongly associated with its ability to interact with membranes of neurons and other cerebral cells. Aβ is derived from amyloidogenic cleavage of amyloid precursor protein (AβPP) by β- and γ-secretase. In the nonamyloidogenic pathway, AβPP is cleaved by α-secretases.

Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate.

Excessive production of Aβ (amyloid β-peptide) has been shown to play an important role in the pathogenesis of AD (Alzheimer's disease). Although not yet well understood, aggregation of Aβ is known to cause toxicity to neurons. Our recent study demonstrated the ability for oligomeric Aβ to stimulate the production of ROS (reactive oxygen species) in neurons through an NMDA (N-methyl-D-aspartate)-dependent pathway.

The role of surface charge on the uptake and biocompatibility of hydroxyapatite nanoparticles with osteoblast cells.

The objective of this study is to evaluate the effect of hydroxyapatite (HAP) nanoparticles with different surface charges on the cellular uptake behavior and in vitro cell viability and proliferation of MC3T3-E1 cell lines (osteoblast). The nanoparticles' surface charge was varied by surface modification with two carboxylic acids: 12-aminododecanoic acid (positive) and dodecanedioic acid (negative). The untreated HAP nanoparticles and dodecanoic acid modified HAP nanoparticles (neutral) were used as the control.

Phospholipases A2 and neural membrane dynamics: implications for Alzheimer's disease.

Phospholipases A(2) (PLA(2)s) are essential enzymes in cells. They are not only responsible for maintaining the structural organization of cell membranes, but also play a pivotal role in the regulation of cell functions. Activation of PLA(2) s results in the release of fatty acids and lysophospholipids, products that are lipid mediators and compounds capable of altering membrane microdomains and physical properties.

Effects of fatty acid unsaturation numbers on membrane fluidity and α-secretase-dependent amyloid precursor protein processing.

Fatty acids may integrate into cell membranes to change physical properties of cell membranes, and subsequently alter cell functions in an unsaturation number-dependent manner. To address the roles of fatty acid unsaturation numbers in cellular pathways of Alzheimer's disease (AD), we systematically investigated the effects of fatty acids on cell membrane fluidity and α-secretase-cleaved soluble amyloid precursor protein (sAPP(α)) secretion in relation to unsaturation numbers using stearic acid (SA, 18:0), oleic acid (OA, 18:1), linoleic acid (LA, 18:2), α-linolenic acid (ALA, 18:3), arachidonic acid (AA, 20:4), eicosapentaenoic acid (EPA, 20:5), and docosahexaenoic acid (DHA, 22:6). Treatments of differentiated human neuroblastoma (SH-SY5Y cells) with AA, EPA and DHA for 24h increased sAPP(α) secretion and membrane fluidity, whereas those treatments with SA, OA, LA and ALA did not.

The impact of vascular endothelial growth factor-transfected human endothelial cells on endothelialization and restenosis of stainless steel stents.

Objectives: The purpose of this study was to investigate the effects of gene transfection of endothelial cells with vascular endothelial growth factor (VEGF) on re-endothelialization and inhibiting in-stent restenosis.

Methods: Stents coated with human umbilical vein endothelial cells (HUVECs) transfected with VEGF(121) were studied both in vitro and in vivo. In vitro studies were performed using a homemade extracorporeal circulation system.

Membrane biophysics and mechanics in Alzheimer's disease.

Alzheimer's disease is a chronic neurodegenerative disorder characterized by neuronal loss, cerebrovascular inflammation, and accumulation of senile plaques in the brain parenchyma and cerebral blood vessels. Amyloid-beta peptide (Abeta), a major component of senile plaques, has been shown to exert multiple toxic effects to neurons, astrocytes, glial cells, and brain endothelium. Oligomeric Abeta can disturb the structure and function of cell membranes and alter membrane mechanical properties, such as membrane fluidity and molecular order.

Secretory phospholipase A2 type III enhances alpha-secretase-dependent amyloid precursor protein processing through alterations in membrane fluidity.

In the non-amyloidogenic pathway, amyloid precursor protein (APP) is cleaved by alpha-secretases to produce alpha-secretase-cleaved soluble APP (sAPP(alpha)) with neuroprotective and neurotrophic properties; therefore, enhancing the non-amyloidogenic pathway has been suggested as a potential pharmacological approach for the treatment of Alzheimer's disease. Here, we demonstrate the effects of type III secretory phospholipase A(2) (sPLA(2)-III) on sAPP(alpha) secretion. Exposing differentiated neuronal cells (SH-SY5Y cells and primary rat neurons) to sPLA(2)-III for 24 h increased sAPP(alpha) secretion and decreased levels of Abeta(1-42) in SH-SY5Y cells, and these changes were accompanied by increased membrane fluidity.

NAD(P)H oxidase-mediated reactive oxygen species production alters astrocyte membrane molecular order via phospholipase A2.

ROS (reactive oxygen species) overproduction is an important underlying factor for the activation of astrocytes in various neuropathological conditions. In the present study, we examined ROS production in astrocytes and downstream effects leading to changes in the signalling cascade, morphology and membrane dynamics using menadione, a redox-active compound capable of inducing intracellular ROS. NAD(P)H oxidase-mediated menadione-induced ROS production, which then stimulated phosphorylation of p38 MAPK (mitogen-activated protein kinase) and ERK1/2 (extracellular-signal-regulated kinase 1/2), and increased actin polymerization and cytoskeletal protrusions.

Electrospun nanofiber meshes with tailored architectures and patterns as potential tissue-engineering scaffolds.

Using a stainless steel mesh as a template collector, electrospun nanofiber meshes with well-tailored architectures and patterns were successfully prepared from biodegradable poly (epsilon-caprolactone) (PCL). It was found that the resulting PCL nanofiber (NF) meshes had similar topological structures to that of the template stainless steel mesh. Such PCL nanofiber meshes (NF meshes) had improved the tensile strength with Young's modulus of 62.

Amyloid-beta peptide induces temporal membrane biphasic changes in astrocytes through cytosolic phospholipase A2.

Oligomeric amyloid-beta peptide (Abeta) is known to induce cytotoxic effects and to damage cell functions in Alzheimer's disease. However, mechanisms underlying the effects of Abeta on cell membranes have yet to be fully elucidated. In this study, Abeta 1-42 (Abeta(42)) was shown to cause a temporal biphasic change in membranes of astrocytic DITNC cells using fluorescence microscopy of Laurdan.

Characterization of changes in the viscosity of lipid membranes with the molecular rotor FCVJ.

Membrane viscosity is a key parameter in cell physiology, cell function, and cell signaling. The most common methods to measure changes in membrane viscosity are fluorescence recovery after photobleaching (FRAP) and fluorescence anisotropy. Recent interest in a group of viscosity sensitive fluorophores, termed molecular rotors, led to the development of the highly membrane-compatible (2-carboxy-2-cyanovinyl)-julolidine farnesyl ester (FCVJ).

Phospholipases A2 mediate amyloid-beta peptide-induced mitochondrial dysfunction.

Mitochondrial dysfunction has been implicated in the pathophysiology of Alzheimer's disease (AD) brains. To unravel the mechanism(s) underlying this dysfunction, we demonstrate that phospholipases A2 (PLA2s), namely the cytosolic and the calcium-independent PLA2s (cPLA2 and iPLA2), are key enzymes mediating oligomeric amyloid-beta peptide (Abeta(1-42))-induced loss of mitochondrial membrane potential and increase in production of reactive oxygen species from mitochondria in astrocytes. Whereas the action of iPLA2 is immediate, the action of cPLA2 requires a lag time of approximately 12-15 min, probably the time needed for initiating signaling pathways for the phosphorylation and translocation of cPLA2 to mitochondria.

Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes.

Excess hydrogen peroxide (H2O2) is produced in the pathogenesis of brain injuries and neurodegenerative diseases. H2O2 may damage cells through direct oxidation of lipids, proteins and DNA or it can act as a signaling molecule to trigger intracellular pathways leading to cell death. In this study, H2O2 caused plasma membranes of primary astrocytes to become more gel-like, while artificial membranes of vesicles composed of rat brain lipid extract became more liquid crystalline-like.

Mechanism of protein sorting during erythroblast enucleation: role of cytoskeletal connectivity.

During erythroblast enucleation, nuclei surrounded by plasma membrane separate from erythroblast cytoplasm. A key aspect of this process is sorting of erythroblast plasma membrane components to reticulocytes and expelled nuclei. Although it is known that cytoskeletal elements actin and spectrin partition to reticulocytes, little is understood about molecular mechanisms governing plasma membrane protein sorting.