Multifunctional Liposomes Targeting Amyloid-β Oligomers for Early Diagnosis and Therapy of Alzheimer's Disease.

Early detection and treatment are crucial for Alzheimer's disease (AD) management. Current diagnostic and therapeutic methods focus on late-stage amyloid fibrils and plaques, overlooking toxic soluble amyloid β oligomers (AβOs) accumulating early in AD. A multifunctional liposome-based platform is designed for early diagnosis and therapy of AD, leveraging a novel self-assembled cyclic d,l-α-peptide (CP-2) that selectively targets AβOs.

Noninvasive Treatment of Alzheimer's Disease with Scintillating Nanotubes.

Effective and accessible treatments for Alzheimer's disease (AD) are urgently needed. Soluble Aβ oligomers are identified as neurotoxic species in AD and targeted in antibody-based drug development to mitigate cognitive decline. However, controversy exists concerning their efficacy and safety.

Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity.

Transient soluble oligomers of amyloid-β (Aβ) are considered among the most toxic species in Alzheimer's disease (AD). Soluble Aβ oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 () self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers.

Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers.

Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g.

Cu-Induced self-assembly and amyloid formation of a cyclic D,L-α-peptide: structure and function.

In a wide spectrum of neurodegenerative diseases, self-assembly of pathogenic proteins to cytotoxic intermediates is accelerated by the presence of metal ions such as Cu. Only low concentrations of these early transient oligomeric intermediates are present in a mixture of species during fibril formation, and hence information on the extent of structuring of these oligomers is still largely unknown. Here, we investigate dimers as the first intermediates in the Cu-driven aggregation of a cyclic D,L-α-peptide architecture.

Glucose-Functionalized Liposomes for Reducing False Positives in Cancer Diagnosis.

Fluorodeoxyglucose-positron emission tomography (F-FDG-PET) is a powerful tool for cancer detection, staging, and follow-up. However, F-FDG-PET imaging has high rates of false positives, as it cannot distinguish between tumor and inflammation regions that both feature increased glucose metabolic activity. In the present study, we engineered liposomes coated with glucose and the chelator dodecane tetraacetic acid (DOTA) complexed with copper, to serve as a diagnostic technology for differentiating between cancer and inflammation.

Bifunctional Carbon Dots-Magnetic and Fluorescent Hybrid Nanoparticles for Diagnostic Applications.

There is a huge demand for materials capable of simple detection or separation after conjugation with specific biologic substances when applied as a diagnostic tools. Taking into account the photoluminescence properties of C-dots and the highly magnetic properties of Fe(0), a new hybrid composite of these components was synthesized via ultrasound irradiation. The material was fully characterized by various physicochemical techniques.

Neuroprotective Effect of Nerve Growth Factor Loaded in Porous Silicon Nanostructures in an Alzheimer's Disease Model and Potential Delivery to the Brain.

Nerve growth factor (NGF) plays a vital role in reducing the loss of cholinergic neurons in Alzheimer's disease (AD). However, its delivery to the brain remains a challenge. Herein, NGF is loaded into degradable oxidized porous silicon (PSiO ) carriers, which are designed to carry and continuously release the protein over a 1 month period.

Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity specific interactions with its histidine residues.

The self-assembly of Aβ to β-sheet-rich neurotoxic oligomers is a main pathological event leading to Alzheimer's disease (AD). Selective targeting of Aβ oligomers without affecting other functional proteins is therefore an attractive approach to prevent the disease and its progression. In this study, we report that photodynamic treatment of Aβ in the presence of catalytic amounts of chlorin e6 can selectively damage Aβ and inhibit its aggregation and toxicity.

Distinct Effects of O-GlcNAcylation and Phosphorylation of a Tau-Derived Amyloid Peptide on Aggregation of the Native Peptide.

Protein phosphorylation and O-GlcNAcylation are very common nucleoplasmic post-translational modifications. Mono-addition of either the phosphate or the O-GlcNAc group were shown to inhibit the self-aggregation of amyloidogenic proteins and peptides, which is the hallmark of various protein misfolding diseases. However, their comparable effect upon co-incubation with a native non-modified amyloid scaffold has not been reported.

Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer.

Invited for this month's cover is Prof. Arie Gruzman (Bar-Ilan University) and collaborators who have developed an Nrf2 enhancer. This compound activated the Nrf2 transduction pathway and because of this the translation of dozens of antioxidant cytoprotective proteins in a dose- and time-dependent manner and protected PC-12 cells against oxidative stress.

Computer-Aided Design and Synthesis of 1-{4-[(3,4-Dihydroxybenzylidene)amino]phenyl}-5-oxopyrrolidine-3-carboxylic Acid as an Nrf2 Enhancer.

The design and synthesis of a novel nuclear factor erythroid 2-related factor 2 (Nrf2) enhancer is reported. Using a structure-based virtual screening approach, several commercially available compounds were identified as having high probability to interact with the Nrf2-binding pocket in the Kelch-like ECH-associated protein 1 (Keap1). Keap1 is an adaptor protein that recruits Nrf2 to a cullin-3-dependent ubiquitin ligase complex.

Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species.

Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, Aβ is found in various cellular locations including membranes.

Self-Assembled Cyclic d,l-α-Peptides as Generic Conformational Inhibitors of the α-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies.

Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic d,l-α-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson's disease associated α-synuclein (α-syn) aggregation to toxic oligomers by an "off-pathway" mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-β component region of α-syn, which are responsible for α-syn's membrane intercalation and self-assembly, thus changing the overall conformation of α-syn.

Sonochemically-Produced Metal-Containing Polydopamine Nanoparticles and Their Antibacterial and Antibiofilm Activity.

A facile one-pot sonochemical synthesis of Cu-, Ag-, and hybrid Cu/Ag-based polydopamine nanoparticles (Cu-, Ag-, and Cu/Ag-PDA-NPs) and the mechanisms by which they exert antibacterial and antibiofilm activities are reported. We showed that the nanoparticles are spherical with a core-shell structure. Whereas Cu is chelated to the shell of Cu-PDA-NPs in oxidation states of +1/+2, the core of Ag-PDA-NPs is filled with elemental Ag°.

Selective Inhibition of Aggregation and Toxicity of a Tau-Derived Peptide using Its Glycosylated Analogues.

Protein glycosylation is a ubiquitous post-translational modification that regulates the folding and function of many proteins. Misfolding of protein monomers and their toxic aggregation are the hallmark of many prevalent diseases. Thus, understanding the role of glycans in protein aggregation is highly important and could contribute both to unraveling the pathology of protein misfolding diseases as well as providing a means for modifying their course for therapeutic purposes.

A versatile water-soluble chelating and radical scavenging platform.

The phenol-diamide compound, 5-(tert-butyl)-2-hydroxy-N1,N3-bis(2-hydroxyethyl)isophthalamide (), is water-soluble, non-cytotoxic, and capable of both, trapping ROS species and chelating Cu(ii) and Fe(iii) ions; these combined properties confer a protective effect against ROS induced cell death.

Resolution of Two Sub-Populations of Conformers and Their Individual Dynamics by Time Resolved Ensemble Level FRET Measurements.

Most active biopolymers are dynamic structures; thus, ensembles of such molecules should be characterized by distributions of intra- or intermolecular distances and their fast fluctuations. A method of choice to determine intramolecular distances is based on Förster resonance energy transfer (FRET) measurements. Major advances in such measurements were achieved by single molecule FRET measurements.

Tubular cell phenotype in HIV-associated nephropathy: role of phospholipid lysophosphatidic acid.

Collapsing glomerulopathy and microcysts are characteristic histological features of HIV-associated nephropathy (HIVAN). We have previously reported the role of epithelial mesenchymal transition (EMT) in the development of glomerular and tubular cell phenotypes in HIVAN. Since persistent tubular cell activation of NFκB has been reported in HIVAN, we now hypothesize that HIV may be contributing to tubular cell phenotype via lysophosphatidic acid (LPA) mediated downstream signaling.

Antibacterial and antibiofilm surfaces through polydopamine-assisted immobilization of lysostaphin as an antibacterial enzyme.

Antibiotic resistance and the colonization of bacteria on surfaces, often as biofilms, prolong hospitalization periods, increase mortality, and are thus major concerns for health care providers. There is an urgent need for antimicrobial and antibiofilm surface treatments that are permanent, can eradicate both biofilms and planktonic pathogens over long periods of time, and do not select for resistant strains. In this study, we have demonstrated a simple, robust, and biocompatible method that utilizes the adhesive property of polydopamine (PDA) to covalently attach the antimicrobial enzyme lysostaphin (Lst) to a variety of surfaces to generate antibacterial and antibiofilm interfaces.

Multifunctional cyclic D,L-α-peptide architectures stimulate non-insulin dependent glucose uptake in skeletal muscle cells and protect them against oxidative stress.

Oxidative stress directly correlates with the early onset of vascular complications and the progression of peripheral insulin resistance in diabetes. Accordingly, exogenous antioxidants augment insulin sensitivity in type 2 diabetic patients and ameliorate its clinical signs. Herein, we explored the unique structural and functional properties of the abiotic cyclic D,L-α-peptide architecture as a new scaffold for developing multifunctional agents to catalytically decompose ROS and stimulate glucose uptake.

Sonochemically produced polydopamine nanocapsules with selective antimicrobial activity.

A facile, versatile, and one-pot sonochemical synthesis of polydopamine (PDA)-nanocapsules from dopamine is reported. The nanocapsules (227 ± 25 nm) can encapsulate hydrophobic substances while retaining the reactivity of PDA toward nucleophilic reactions, enabling facile surface modification for different applications. PDA nanocapsules are nontoxic to mammalian cells while Cu-containing PDA capsules demonstrate strong (99.

In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic D,L-α-peptide architecture.

Misfolding of the Aβ protein and its subsequent aggregation into toxic oligomers are related to Alzheimer's disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self-assembled cyclic D,L-α-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of Aβ, thereby preventing its aggregation into toxic forms.

Effective targeting of Aβ to macrophages by sonochemically prepared surface-modified protein microspheres.

Imbalanced homeostasis and oligomerization of the amyloid-β (Aβ) peptide in the brain are hallmarks of Alzheimer's disease (AD). Microglia and macrophages play a critical role in the etiology of AD either by clearing Aβ from the brain or inducing inflammation. Recent evidence suggests that clearance of Aβ by microglia/macrophages via the phagocytic pathway is defective in AD, which can contribute to the accumulation of Aβ in the brain.

Surface-modified protein nanospheres as potential antiviral agents.

A novel application of surface-modified protein nanospheres as potential antiviral agents is illustrated. By using a single-step sonochemical process, bovine serum albumin nanospheres were generated, whose surface was covalently conjugated with mercaptoethane sulfonate to chemically and electrostatically mimic cellular heparan sulfate. The nanospheres effectively inhibited HSV-1 infection.