Amyloid beta 1-40 and 1-42 fibril ratios and maturation level cause conformational differences with minimal impact on autophagy and cytotoxicity.

The amyloid β (Aβ) peptide has a central role in Alzheimer's disease (AD) pathology. The peptide length can vary between 37 and 49 amino acids, with Aβ1-42 being considered the most disease-related length. However, Aβ1-40 is also found in Aβ plaques and has shown to form intertwined fibrils with Aβ1-42.

Virtual Reality for the Management of Pain and Anxiety for IR Procedures: A Prospective, Randomized, Pilot Study on Digital Sedation.

Purpose: To assess the analgesic and anxiolytic effects of virtual reality (VR) augmentation in patients undergoing peripherally inserted central catheter (PICC) placement or fine-needle aspiration thyroid biopsy.

Materials And Methods: This is a prospective, single-center randomized controlled trial with 107 patients enrolled. Patients were randomly assigned to receive standard of care (SOC) or SOC+VR during PICC or thyroid biopsy procedures.

Radiosynthesis, and Evaluation of [F]CBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [H]CBD-2115 had a value of 6.9 nM and a nominal of 500 nM in 4R-tau expressing P301L transgenic mouse tissue.

Fibrillation and molecular characteristics are coherent with clinical and pathological features of 4-repeat tauopathy caused by MAPT variant G273R.

Microtubule Associated Protein Tau (MAPT) forms proteopathic aggregates in several diseases. The G273R tau mutation, located in the first repeat region, was found by exome sequencing in a patient who presented with dementia and parkinsonism. We herein return to pathological examination which demonstrated tau immunoreactivity in neurons and glia consistent of mixed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) features.

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.

Purification and Fibrillation of Recombinant Human Amyloid-β, Prion Protein, and Tau Under Native Conditions.

Protein misfolding, aggregation, and amyloid formation is involved in a large number of diseases. Recombinantly expressed proteins to study the amyloid fibril formation process are important for mechanistic studies. We here report protocols for production, purification, and fibrillation of three different proteins commonly found in cerebral amyloid; Aβ and Tau found in Alzheimer's disease, Chronic traumatic brain injury, Corticobasal degeneration, and Progressive Supranuclear Palsy and human prion protein found in Creutzfeldt-Jakob's disease.

Aggregated Aβ1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila.

The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human Aβ1-42 associated with Alzheimer's disease.

Detection and Imaging of Aβ1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues.

We revisited the Congo red analogue 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimer's disease (AD) pathology comprising Aβ and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes.

-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils.

It was previously reported that two naphthyl-based -stilbene probes, ()-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol () and ()-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (), can bind to both native transthyretin (TTR) and misfolded protofibrillar TTR at physiological concentrations, displaying distinct emission maxima bound to the different conformational states (>100 nm difference). To further explore this amyloid probe scaffold to obtain extended fluorescence lifetimes, two new analogues with expanded aromatic ring systems (anthracene and pyrene), ()-4-(2-(anthracen-2-yl)vinyl)benzene-1,2-diol () and ()-4-(2-(pyren-2-yl)vinyl)benzene-1,2-diol (), were synthesized employing the palladium-catalyzed Mizoroki-Heck reaction. ()-4-Styrylbenzene-1,2-diol (), , , and were investigated with respect to their photophysical properties in methanol and when bound to insulin, lysozyme, and Aβ1-42 fibrils, including time-resolved fluorescence measurements.