In Vitro Cell Model Investigation of Alpha-Synuclein Aggregate Morphology Using Spectroscopic Imaging.

Recently, it has been hypothesized that alpha-synuclein protein strain morphology may be associated with clinical subtypes of alpha-synucleinopathies, like Parkinson's disease and multiple system atrophy. However, direct evidence is lacking due to the caveat of conformation-specific characterization of protein strain morphology. Here we present a new cell model based in vitro method to explore various alpha-synuclein (αsyn) aggregate morphotypes.

Polyallylamine Binds to Aβ Amyloid and Inhibits Antibody Recognition.

Protein amyloids have attracted attention for their application as functional amyloid materials because of their strong properties, such as high resistance to chemical or biological degradation, despite their medical issues. Amyloids can be used for various applications by modifying the amyloid surface with functional materials, such as proteins and polymers. In this study, we investigated the effect of polyallylamine (PAA), a functional cationic polymer as a candidate for amyloid modification, on the amyloids formed from amyloid β (Aβ) peptide.

Kinetic effects in singlet oxygen mediated oxidations by immobilized photosensitizers on silica.

Singlet oxygen (O) mediated photo-oxidations are important reactions involved in numerous processes in chemical and biological sciences. While most of the current research works have aimed at improving the efficiencies of these transformations either by increasing O quantum yields or by enhancing its lifetime, we establish herein that immobilization of a molecular photosensitizer onto silica surfaces affords significant, substrate dependant, enhancement in the reactivity of O. Probing a classical model reaction (oxidation of Anthracene-9, 10-dipropionic acid, ADPA or dimethylanthracene, DMA) with various spectrofluorimetric techniques, it is here proposed that an interaction between polar substrates and the silica surface is responsible for the observed phenomenon.

A fluorescence spectroscopic study of light transmission and adaxial-abaxial distribution of emitting compounds in leaves of Christmas star (Euphorbia pulcherrima).

In situ fluorescence measurements have been used to investigate relative amounts of blue-green pigments and their distributions in plant leaves from Euphorbia pulcherrima. Advantage was taken from the fact that this species has white leaves on the top, with low pigment concentrations, and green leaves on the stem with ordinary pigment concentrations. Excitation- and emission spectra below 410 nm from white leaves, where pigment absorption is low, are not distorted by self-absorption.

Binding of a Pyrene-Based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study.

Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes.

targeting and multimodal imaging of cerebral amyloid-β aggregates using hybrid GdF nanoparticles.

To propose a new multimodal imaging agent targeting amyloid-β (Aβ) plaques in Alzheimer's disease. A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer's disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution.

ApoE Alzheimer's Disease Aβ-amyloid plaque morphology varies according to APOE isotype.

Background: The apolipoprotein E (, gene; apoE, protein) ε4 allele is the most common identified genetic risk factor for typical late-onset sporadic Alzheimer's disease (AD). Each ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, ε3.

Methods: We have employed hyperspectral fluorescence imaging with an amyloidspecific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either ε3 or ε4.

Self-Assembly of Chiro-Optical Materials from Nonchiral Oligothiophene-Porphyrin Derivatives and Random Coil Synthetic Peptides.

Biomimetic chiral optoelectronic materials can be utilized in electronic devices, biosensors and artificial enzymes. Herein, this work reports the chiro-optical properties and architectural arrangement of optoelectronic materials generated from self-assembly of initially nonchiral oligothiophene-porphyrin derivatives and random coil synthetic peptides. The photo-physical- and structural properties of the materials were assessed by absorption-, fluorescence- and circular dichroism spectroscopy, as well as dynamic light scattering, scanning electron microscopy and theoretical calculations.

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies.

Pathogenic alpha-synuclein (asyn) aggregates are a defining feature of neurodegenerative synucleinopathies, which include Parkinson's disease, Lewy body dementia, pure autonomic failure and multiple system atrophy. Early accurate differentiation between these synucleinopathies is challenging due to the highly heterogeneous clinical profile at early prodromal disease stages. Therefore, diagnosis is often made in late disease stages when a patient presents with a broad range of motor and non-motor symptoms easing the differentiation.

Amphiphilic Protoporphyrin IX Derivatives as New Photosensitizing Agents for the Improvement of Photodynamic Therapy.

Photodynamic therapy (PDT) is a non-invasive therapeutic modality based on the interaction between a photosensitive molecule called photosensitizer (PS) and visible light irradiation in the presence of oxygen molecule. Protoporphyrin IX (PpIX), an efficient and widely used PS, is hampered in clinical PDT by its poor water-solubility and tendency to self-aggregate. These features are strongly related to the PS hydrophilic-lipophilic balance.

Tau Protein Binding Modes in Alzheimer's Disease for Cationic Luminescent Ligands.

The bi-thiophene-vinylene-benzothiazole (bTVBT4) ligand developed for Alzheimer's disease (AD)-specific detection of amyloid tau has been studied by a combination of several theoretical methods and experimental spectroscopies. With reference to the cryo-EM tau structure of the tau protofilament ( 2017, 547, 185), a periodic model system of the fibril was created, and the interactions between this fibril and bTVBT4 were studied with nonbiased molecular dynamics simulations. Several binding sites and binding modes were identified and analyzed, and the results for the most prevailing fibril site and ligand modes are presented.

Degradation of insulin amyloid by antibiotic minocycline and formation of toxic intermediates.

Insulin balls, localized insulin amyloids formed at subcutaneous insulin-injection sites in patients with diabetes, cause poor glycemic control owing to impairments in insulin absorption. Our previous study has shown that some insulin balls are cytotoxic, but others are not, implying amyloid polymorphism. Interestingly, the patient with toxic insulin balls had been treated with antibiotic minocycline, suggesting a possible relationship between toxicity of insulin balls and minocycline.

Hybrid multimodal contrast agent for multiscale investigation of neuroinflammation.

Neuroinflammation is a process common to several brain pathologies. Despites its medical relevance, it still remains poorly understood; there is therefore a need to develop new in vivo preclinical imaging strategies to monitor inflammatory processes longitudinally. We here present the development of a hybrid imaging nanoprobe named NP3, that was specifically designed to get internalized by phagocytic cells and imaged in vivo with MRI and bi-photon microscopy.

Fluorescent Nanocomposites: Hollow Silica Microspheres with Embedded Carbon Dots.

Intrinsically fluorescent carbon dots may form the basis for a safer and more accurate sensor technology for digital counting in bioanalytical assays. This work presents a simple and inexpensive synthesis method for producing fluorescent carbon dots embedded in hollow silica particles. Hydrothermal treatment at low temperature (160 °C) of microporous silica particles in presence of urea and citric acid results in fluorescent, microporous and hollow nanocomposites with a surface area of 12 m /g.

Deciphering the Electronic Transitions of Thiophene-Based Donor-Acceptor-Donor Pentameric Ligands Utilized for Multimodal Fluorescence Microscopy of Protein Aggregates.

Anionic pentameric thiophene acetates can be used for fluorescence detection and diagnosis of protein amyloid aggregates. Replacing the central thiophene unit by benzothiadiazole (BTD) or quinoxaline (QX) leads to large emission shifts and basic spectral features have been reported [Chem. Eur.

Tyrosine Side-Chain Functionalities at Distinct Positions Determine the Chirooptical Properties and Supramolecular Structures of Pentameric Oligothiophenes.

Control over the photophysical properties and molecular organization of π-conjugated oligothiophenes is essential to their use in organic electronics. Herein we synthesized and characterized a variety of anionic pentameric oligothiophenes with different substitution patterns of L- or D-tyrosine at distinct positions along the thiophene backbone. Spectroscopic, microscopic, and theoretical studies of L- or D-tyrosine substituted pentameric oligothiophene conjugates revealed the formation of optically active π-stacked self-assembled aggregates under acid conditions.

Insulin amyloid polymorphs: implications for iatrogenic cytotoxicity.

Amyloid specific fluorescent probes are becoming an important tool for studies of disease progression and conformational polymorphisms in diseases related to protein misfolding and aggregation such as localized and systemic amyloidosis. Herein, it is demonstrated that using the amyloid specific fluorescent probes pFTAA and benzostyryl capped benzothiadiazole BTD21, structural polymorphisms of insulin amyloids are imaged in localized insulin-derived amyloid aggregates formed at subcutaneous insulin-injection sites in patients with diabetes. It is also found that pFTAA and BTD21 could discriminate structural polymorphisms of insulin amyloids, so called fibrils and filaments, formed .

Influence of Polymer Charge on the Localization and Dark- and Photo-Induced Toxicity of a Potential Type I Photosensitizer in Cancer Cell Models.

A current trend within photo-dynamic therapy (PDT) is the development of molecular systems targeting hypoxic tumors. Thus, type I PDT sensitizers could here overcome traditional type II molecular systems that rely on the photo-initiated production of toxic singlet oxygen. Here, we investigate the cell localization properties and toxicity of two polymeric anthracene-based fluorescent probes (neutral Ant-PHEA and cationic Ant-PIm).

Phenolic Bis-styrylbenzo[ c]-1,2,5-thiadiazoles as Probes for Fluorescence Microscopy Mapping of Aβ Plaque Heterogeneity.

A fluorescent bis-styryl-benzothiadiazole (BTD) with carboxylic acid functional groups (X-34/Congo red analogue) showed lower binding affinity toward Aβ1-42 and Aβ1-40 fibrils than its neutral analogue. Hence, variable patterns of neutral OH-substituted bis-styryl-BTDs were generated. All bis-styryl-BTDs showed higher binding affinity to Aβ1-42 fibrils than to Aβ1-40 fibrils.

Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.

Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule.

Two-Photon Fluorescence and Magnetic Resonance Specific Imaging of Aβ Amyloid Using Hybrid Nano-GdF Contrast Media.

Real time detection of Amyloid β (Aβ) deposits at an early stage may lead to faster and more conclusive diagnosis of Alzheimer's disease (AD) and can facilitate the follow up of the effect of therapeutic interventions. In this work, the capability of new hybrid nanomaterials to target and detect Aβ aggregates using magnetic resonance (MRI) and fluorescence imaging is demonstrated. These smart contrast agents contain paramagnetic nanoparticles surrounded by luminescent conjugated oligothiophenes (LCOs) known to selectively bind to Aβ aggregates, with emission spectra strongly dependent on their conformations, opening the possibilities for several fluorescence imaging modes for AD diagnostics.

Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents.

Small molecules with modalities for a variety of imaging techniques as well as therapeutic activity are essential, as such molecules render opportunities to simultaneously conduct diagnosis and targeted therapy, so called theranostics. In this regard, glycoporphyrins have proven useful as theranostic agents towards cancer, as well as noncancerous conditions. Herein, the synthesis and characterization of heterobifunctional glycoconjugated porphyrins with two different sugar moieties, a common monosaccharide at three sites, and a 2-fluoro-2-deoxy glucose (FDG) moiety at the fourth site are presented.

Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents.

Invited for this month's cover picture is the group of Professor Peter Nilsson at the Department of Physics, Chemistry and Biology at Linköping University (Sweden). The cover picture shows a fluoro-glycoporphyrin that selectively targets cancer cells. The selectivity towards cancer cells are afforded due to proper functionalization of the porphyrin scaffold with specific carbohydrates, and the cancer cells can be visualized because of the intrinsic fluorescence from the porphyrin.

Luminescent-Conjugated Oligothiophene Probe Applications for Fluorescence Imaging of Pure Amyloid Fibrils and Protein Aggregates in Tissues.

Luminescent-conjugated oligo- and polythiophenes (LCOs and LCPs) are valuable tools for optical imaging of a plethora of protein aggregates associated with amyloidoses. Here, we outline updated protocols for the application of the anionic pentameric LCO, p-FTAA, for staining and hyperspectral imaging of protein aggregates in a variety of settings such as in vitro formed amyloid fibrils, ex vivo tissue sections, and whole brain Drosophila.