Blood-based quantification of Aβ oligomers indicates impaired clearance from brain in ApoE ε4 positive subjects.

Background: Quantification of Amyloid beta (Aβ) oligomers in plasma enables early diagnosis of Alzheimer's Disease (AD) and improves our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology because of very low Aβ oligomer concentrations and possible interference from matrix components.

Methods: In this report, we developed and validated a surface-based fluorescence distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma.

Accurate design of high-affinity protein binding macrocycles using deep learning.

The development of macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource-intensive and provide little control over binding mode. Despite considerable progress in physics-based methods for peptide design and deep-learning methods for protein design, there are currently no robust approaches for design of protein-binding macrocycles. Here, we introduce RFpeptides, a denoising diffusion-based pipeline for designing macrocyclic peptide binders against protein targets of interest.

Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP.

We report the first structure-activity studies of arylidene-indolinone compound which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP.

Elevated Aβ aggregates in feces from Alzheimer's disease patients: a proof-of-concept study.

Background: Misfolding and aggregation of amyloid β (Aβ), along with neurofibrillary tangles consisting of aggregated Tau species, are pathological hallmarks of Alzheimer's disease (AD) onset and progression. In this study, we hypothesized the clearance of Aβ aggregates from the brain and body into the gut.

Methods: To investigate this, we used surface-based fluorescence intensity distribution analysis (sFIDA) to determine the Aβ aggregate concentrations in feces from 26 AD patients and 31 healthy controls (HC).

IAPP - oligomerisation levels in plasma of people with type 2 diabetes.

Islet amyloid polypeptide (IAPP) is co-secreted with insulin from pancreatic ß-cells. Its oligomerisation is regarded as disease driving force in type 2 diabetes (T2D) pathology. Up to now, IAPP oligomers have been detected in affected tissues.

GABARAP interacts with EGFR - supporting the unique role of this hAtg8 protein during receptor trafficking.

The human Atg8 family member GABARAP is involved in numerous autophagy-related and -unrelated processes. We recently observed that specifically the deficiency of GABARAP enhances epidermal growth factor receptor (EGFR) degradation upon ligand stimulation. Here, we report on two putative LC3-interacting regions (LIRs) within EGFR, the first of which (LIR1) is selected as a GABARAP binding site in silico.

Structure and dimerization properties of the plant-specific copper chaperone CCH.

Copper chaperones of the ATX1 family are found in a wide range of organisms where these essential soluble carriers strictly control the transport of monovalent copper across the cytoplasm to various targets in diverse cellular compartments thereby preventing detrimental radical formation catalyzed by the free metal ion. Notably, the ATX1 family in plants contains two distinct forms of the cellular copper carrier. In addition to ATX1 having orthologs in other species, they also contain the copper chaperone CCH.

Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.

Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1 by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1-specific disease mechanism provoking cardiac hypertrophy.

A Snake Venom Peptide and Its Derivatives Prevent Aβ Aggregation and Eliminate Toxic Aβ Aggregates .

Over a century has passed since Alois Alzheimer first described Alzheimer's disease (AD), and since then, researchers have made significant strides in understanding its pathology. One key feature of AD is the presence of amyloid-β (Aβ) peptides, which form amyloid plaques, and therefore, it is a primary target for treatment studies. Naturally occurring peptides have garnered attention for their potential pharmacological benefits, particularly in the central nervous system.

TSAT: Efficient evaluation software for NGS data of phage/mirror-image phage display selections.

Phage display and mirror-image phage display are commonly used techniques for the identification of binders that are specific to predefined targets. Recent studies demonstrated the effectiveness of next-generation sequencing (NGS) by increasing the amount of information extracted from selections. This allows for a better analysis and increases the possibility to select effective binders.

Aβ oligomers peak in early stages of Alzheimer's disease preceding tau pathology.

Introduction: Soluble amyloid beta (Aβ) oligomers have been suggested as initiating Aβ related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear.

Methods: A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aβ and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface-based fluorescence intensity distribution analysis (sFIDA) technology.

Large dynamics of a phase separating arginine-glycine-rich domain revealed via nuclear and electron spins.

Liquid-liquid phase separation is the key process underlying formation of membrane-less compartments in cells. A highly dynamic cellular body with rapid component exchange is Cajal body (CB), which supports the extensive compositional dynamics of the RNA splicing machinery, spliceosome. Here, we select an arginine-glycine (RG)-rich segment of coilin, the major component of CB, establish its RNA-induced phase separation, and through combined use of nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) probes, interrogate its dynamics within the crowded interior of formed droplets.

Conserved Signal Transduction Mechanisms and Dark Recovery Kinetic Tuning in the Pseudomonadaceae Short Light, Oxygen, Voltage (LOV) Protein Family.

Light-Oxygen-Voltage (LOV) flavoproteins transduce a light signal into variable signaling outputs via a structural rearrangement in the sensory core domain, which is then relayed to fused effector domains via α-helical linker elements. Short LOV proteins from Pseudomonadaceae consist of a LOV sensory core and N- and C-terminal α-helices of variable length, providing a simple model system to study the molecular mechanism of allosteric activation. Here we report the crystal structures of two LOV proteins from Pseudomonas fluorescens - SBW25-LOV in the fully light-adapted state and Pf5-LOV in the dark-state.

Sequence-based identification of amyloidogenic β-hairpins reveals a prostatic acid phosphatase fragment promoting semen amyloid formation.

β-Structure-rich amyloid fibrils are hallmarks of several diseases, including Alzheimer's (AD), Parkinson's (PD), and type 2 diabetes (T2D). While amyloid fibrils typically consist of parallel β-sheets, the anti-parallel β-hairpin is a structural motif accessible to amyloidogenic proteins in their monomeric and oligomeric states. Here, to investigate implications of β-hairpins in amyloid formation, potential β-hairpin-forming amyloidogenic segments in the human proteome were predicted based on sequence similarity with β-hairpins previously observed in Aβ, α-synuclein, and islet amyloid polypeptide, amyloidogenic proteins associated with AD, PD, and T2D, respectively.

An orally available Ca2.2 calcium channel inhibitor for the treatment of neuropathic pain.

Background And Purpose: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid-resistant properties. Therefore, its clinical management remains very challenging.

Cryo-EM of Aβ fibrils from mouse models find tg-APP fibrils resemble those found in patients with sporadic Alzheimer's disease.

The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment of new treatment strategies for Alzheimer's disease. However, the properties of Aβ in such mice have not been systematically compared to Aβ in the brains of patients with Alzheimer's disease. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryogenic-electron microscopy.

The Avidity of Autoreactive Alpha-Synuclein Antibodies in Leucine-Rich Repeat Kinase 2 Mutation Carriers Is Not Altered Compared to Healthy Controls or Patients with Parkinson's Disease.

Unlabelled: The accumulation and aggregation of alpha-synuclein (α-Syn) are pathological processes associated with Parkinson's disease, indicating that the regulation of protein is a crucial etiopathological mechanism. Interestingly, human serum and cerebrospinal fluid contain autoantibodies that recognize α-Syn. This potentially demonstrates an already existing, naturally decomposing, and protective system.

Disrupted-in-schizophrenia 1 protein aggregates in cerebrospinal fluid are elevated in patients with first-episode psychosis.

Aim: The disrupted-in-schizophrenia 1 (DISC1) protein is a key regulator at the intersection of major signaling pathways relevant for adaptive behavior. It is prone to posttranslational changes such as misassembly and aggregation but the significance of such transformations for human mental illness has remained unclear. We aimed to demonstrate the occurrence of DISC1 protein aggregates in patients with first-episode psychosis (FEP).

Oral treatment with the all-d-peptide RD2 enhances cognition in aged beagle dogs - A model of sporadic Alzheimer's disease.

Disease-modifying therapies to treat Alzheimer's disease (AD) are of fundamental interest for aging humans, societies, and health care systems. Predictable disease progression in transgenic AD models favors preclinical studies employing a preventive study design with an early pre-symptomatic treatment start, instead of assessing a truly curative approach with treatment starting after diagnosed disease onset. The aim of this study was to investigate the pharmacokinetic profile and efficacy of RD2 to enhance short-term memory and cognition in cognitively impaired aged Beagle dogs - a non-transgenic model of truly sporadic AD.

Tau protein aggregation associated with SARS-CoV-2 main protease.

The primary function of virus proteases is the proteolytic processing of the viral polyprotein. These enzymes can also cleave host cell proteins, which is important for viral pathogenicity, modulation of cellular processes, viral replication, the defeat of antiviral responses and modulation of the immune response. It is known that COVID-19 can influence multiple tissues or organs and that infection can damage the functionality of the brain in multiple ways.

Development and Implementation of an Internal Quality Control Sample to Standardize Oligomer-Based Diagnostics of Alzheimer's Disease.

Protein misfolding and aggregation are pathological hallmarks of various neurodegenerative diseases. In Alzheimer's disease (AD), soluble and toxic amyloid-β (Aβ) oligomers are biomarker candidates for diagnostics and drug development. However, accurate quantification of Aβ oligomers in bodily fluids is challenging because extreme sensitivity and specificity are required.

Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2-5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients' benefit.

The Importance of Epigallocatechin as a Scaffold for Drug Development against Flaviviruses.

Arboviruses such as Dengue, yellow fever, West Nile, and Zika are flaviviruses vector-borne RNA viruses transmitted biologically among vertebrate hosts by blood-taking vectors. Many flaviviruses are associated with neurological, viscerotropic, and hemorrhagic diseases, posing significant health and socioeconomic concerns as they adapt to new environments. Licensed drugs against them are currently unavailable, so searching for effective antiviral molecules is still necessary.

Evaluation of the F-labeled analog of the therapeutic all-D-enantiomeric peptide RD2 for amyloid β imaging.

Positron emission tomography (PET) imaging with radiotracers that bind to fibrillary amyloid β (Aβ) deposits is an important tool for the diagnosis of Alzheimer's disease (AD) and for the recruitment of patients into clinical trials. However, it has been suggested that rather than the fibrillary Aβ deposits, it is smaller, soluble Aβ aggregates that exert a neurotoxic effect and trigger AD pathogenesis. The aim of the current study is to develop a PET probe that is capable of detecting small aggregates and soluble Aβ oligomers for improved diagnosis and therapy monitoring.

Stabilization of Monomeric Tau Protein by All D-Enantiomeric Peptide Ligands as Therapeutic Strategy for Alzheimer's Disease and Other Tauopathies.

Alzheimer's disease and other tauopathies are the world's leading causes of dementia and memory loss. These diseases are thought to be caused by the misfolding and aggregation of the intracellular tau protein, ultimately leading to neurodegeneration. The tau protein is involved in a multitude of different neurodegenerative diseases.