Harmonizing the Generation and Pre-publication Stewardship of FAIR Image data.

Together with the molecular knowledge of genes and proteins, biological images promise to significantly enhance the scientific understanding of complex cellular systems and to advance predictive and personalized therapeutic products for human health. For this potential to be realized, quality-assured image data must be shared among labs at a global scale to be compared, pooled, and reanalyzed, thus unleashing untold potential beyond the original purpose for which the data was generated. There are two broad sets of requirements to enable image data sharing in the life sciences. One set of requirements is articulated in the companion White Paper entitled "Enabling Global Image Data Sharing in the Life Sciences," which is published in parallel and addresses the need to build the cyberinfrastructure for sharing the digital array data (arXiv:2401.13023 [q-bio.OT], https://doi.org/10.48550/arXiv.2401.13023). In this White Paper, we detail a broad set of requirements, which involves collecting, managing, presenting, and propagating contextual information essential to assess the quality, understand the content, interpret the scientific implications, and reuse image data in the context of the experimental details. We start by providing an overview of the main lessons learned to date through international community activities, which have recently made considerable progress toward generating community standard practices for imaging Quality Control (QC) and metadata. We then provide a clear set of recommendations for amplifying this work. The driving goal is to address remaining challenges, and democratize access to common practices and tools for a spectrum of biomedical researchers, regardless of their expertise, access to resources, and geographical location.

Setting up a state-of-the-art laboratory in resource limited settings: A case study of the biomedical science research and training centre in Northeast Nigeria.

African science has substantial potential, yet it grapples with significant challenges. Here we describe the establishment of the Biomedical Science Research and Training Centre (BioRTC) in Yobe State, Northeast Nigeria, as a case study of a hub fostering on-continent research and describe strategies to overcome current barriers. We detail the steps taken to establish BioRTC, emphasising the critical importance of stakeholder engagement, community involvement, resource optimisation and collaborations. With its state-of-the-art facilities and commitment to training African scientists, BioRTC is poised to significantly advance neuroscience research and training in the region. Although we are in the early stages of our journey, our model, emphasizing open access and inclusivity, offers a replicable blueprint for neuroscience research development in similar resource-limited settings, promising to enrich the global neuroscience community. We invite the support and collaboration of those who share our vision and believe in our potential.

In Silico Identification of a Potential TNF-Alpha Binder Using a Structural Similarity: A Potential Drug Repurposing Approach to the Management of Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder with no conclusive remedy. Yohimbine, found in Rauwolfia vomitoria, may reduce brain inflammation by targeting tumour necrosis factor-alpha (TNFα), implicated in AD pathogenesis. Metoserpate, a synthetic compound, may inhibit TNFα. The study is aimed at assessing the potential utility of repurposing metoserpate for TNFα inhibition to reduce neuronal damage and inflammation in AD. The development of safe and effective treatments for AD is crucial to address the growing burden of the disease, which is projected to double over the next two decades. Methods: Our study repurposed an FDA-approved drug as TNFα inhibitor for AD management using structural similarity studies, molecular docking, and molecular dynamics simulations. Yohimbine was used as a reference compound. Molecular docking used SeeSAR, and molecular dynamics simulation used GROMACS. Results: Metoserpate was selected from 10 compounds similar to yohimbine based on pharmacokinetic properties and FDA approval status. Molecular docking and simulation studies showed a stable interaction between metoserpate and TNFα over 100 ns (100000 ps). This suggests a reliable and robust interaction between the protein and ligand, supporting the potential utility of repurposing metoserpate for TNFα inhibition in AD treatment. Conclusion: Our study has identified metoserpate, a previously FDA-approved antihypertensive agent, as a promising candidate for inhibiting TNFα in the management of AD.

Novel avenues of tau research.

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.

Dityrosine cross-linking and its potential roles in Alzheimer's disease.

Oxidative stress is a significant source of damage that accumulates during aging and contributes to Alzheimer's disease (AD) pathogenesis. Oxidation of proteins can give rise to covalent links between adjacent tyrosines known as dityrosine (DiY) cross-linking, amongst other modifications, and this observation suggests that DiY could serve as a biomarker of accumulated oxidative stress over the lifespan. Many studies have focused on understanding the contribution of DiY to AD pathogenesis and have revealed that DiY crosslinks can be found in both Aß and tau deposits - the two key proteins involved in the formation of amyloid plaques and tau tangles, respectively. However, there is no consensus yet in the field on the impact of DiY on Aß and tau function, aggregation, and toxicity. Here we review the current understanding of the role of DiY on Aß and tau gathered over the last 20 years since the first observation, and discuss the effect of this modification for Aß and tau aggregation, and its potential as a biomarker for AD.

Shapeshifting tau: from intrinsically disordered to paired-helical filaments.

Tau is an intrinsically disordered protein that has the ability to self-assemble to form paired helical and straight filaments in Alzheimer's disease, as well as the ability to form additional distinct tau filaments in other tauopathies. In the presence of microtubules, tau forms an elongated form associated with tubulin dimers via a series of imperfect repeats known as the microtubule binding repeats. Tau has recently been identified to have the ability to phase separate in vitro and in cells. The ability of tau to adopt a wide variety of conformations appears fundamental both to its biological function and also its association with neurodegenerative diseases. The recently highlighted involvement of low-complexity domains in liquid-liquid phase separation provides a critical link between the soluble function and the insoluble dysfunctional properties of tau.

Dityrosine Cross-links are Present in Alzheimer's Disease-derived Tau Oligomers and Paired Helical Filaments (PHF) which Promotes the Stability of the PHF-core Tau (297-391) In Vitro.

A characteristic hallmark of Alzheimer's Disease (AD) is the pathological aggregation and deposition of tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs). Oxidative stress is an early event during AD pathogenesis and is associated with tau-mediated AD pathology. Oxidative environments can result in the formation of covalent dityrosine crosslinks that can increase protein stability and insolubility. Dityrosine cross-linking has been shown in Aß plaques in AD and α-synuclein aggregates in Lewy bodies in ex vivo tissue sections, and this modification may increase the insolubility of these aggregates and their resistance to degradation. Using the PHF-core tau fragment (residues 297 - 391) as a model, we have previously demonstrated that dityrosine formation traps tau assemblies to reduce further elongation. However, it is unknown whether dityrosine crosslinks are found in tau deposits in vivo in AD and its relevance to disease mechanism is unclear. Here, using transmission electron microscope (TEM) double immunogold-labelling, we reveal that neurofibrillary NFTs in AD are heavily decorated with dityrosine crosslinks alongside tau. Single immunogold-labelling TEM and fluorescence spectroscopy revealed the presence of dityrosine on AD brain-derived tau oligomers and fibrils. Using the tau (297-391) PHF-core fragment as a model, we further showed that prefibrillar tau species are more amenable to dityrosine crosslinking than tau fibrils. Dityrosine formation results in heat and SDS stability of oxidised prefibrillar and fibrillar tau assemblies. This finding has implications for understanding the mechanism governing the insolubility and toxicity of tau assemblies in vivo.

A Review of African Medicinal Plants and Functional Foods for the Management of Alzheimer's Disease-related Phenotypes, Treatment of HSV-1 Infection and/or Improvement of Gut Microbiota.

Alzheimer's disease (AD), which is a progressive neurodegenerative disorder is the most common form of dementia globally. Several studies have suggested alteration in the gut microbiota and HSV-1 infection as contributing factors to the development of the disease. As at now, there are no AD attenuating agents and AD pharmacotherapy is focused on managing symptoms while plants used in ethnomedicine remain potential sources of drugs for the treatment of the condition. Here, we reviewed published databases for African ethnomedicinal plants and functional foods of African origin that are used in the management of AD-related phenotypes, treatment of herpes simplex virus -1 (HSV-1) and/or improvement of gut microbiota. A total of 101 unique plant species and 24 different types of traditionally prepared African functional foodstuff were identified. Of the 101 identified plant species, 50 species serve as functional foodstuffs. Twenty-three (23) of the ethnomedicinal plant families were successfully identified for the treatment and management of AD-related phenotypes and age-related dementia. Eighteen (18) African plant species from 15 families were also identified as potent remedies for HSV-1; while many African wild fruits (3 species), roots and tubers (7 species), leafy vegetables (14 species), and seaweeds (26 species) were functional foods for modifying AD-related phenotypes. It was concluded that African medicinal plants are potential sources of both AD attenuating agents and phytocompounds that may be used against HSV-1 infection and alteration of gut microbiota. Additionally, a number of African functional foods are important sources of prebiotics and probiotics.

What is next in African neuroscience?

Working in Africa provides neuroscientists with opportunities that are not available in other continents. Populations in this region exhibit the greatest genetic diversity; they live in ecosystems with diverse flora and fauna; and they face unique stresses to brain health, including child brain health and development, due to high levels of traumatic brain injury and diseases endemic to the region. However, the neuroscience community in Africa has yet to reach its full potential. In this article we report the outcomes from a series of meetings at which the African neuroscience community came together to identify barriers and opportunities, and to discuss ways forward. This exercise resulted in the identification of six domains of distinction in African neuroscience: the diverse DNA of African populations; diverse flora, fauna and ecosystems for comparative research; child brain health and development; the impact of climate change on mental and neurological health; access to clinical populations with important conditions less prevalent in the global North; and resourcefulness in the reuse and adaption of existing technologies and resources to answer new questions. The article also outlines plans to advance the field of neuroscience in Africa in order to unlock the potential of African neuroscientists to address regional and global mental health and neurological problems.

Bypassing shortages of personal protective equipment in low-income settings using local production and open source tools.

Free and open-source hardware, 3D printing, and the use of locally sourced materials can be valuable tools for local problem solving, as proven by the production of more than 400 reusable face shields and masks in a Nigerian community to bypass PPE shortages during the COVID-19 pandemic.

Synthesis, physicochemical characterization and neuroprotective evaluation of novel 1-hydroxypyrazin-2(1H)-one iron chelators in an in vitro cell model of Parkinson's disease.

Iron dysregulation, dopamine depletion, cellular oxidative stress and α-synuclein protein mis-folding are key neuronal pathological features seen in the progression of Parkinson's disease. Iron chelators endowed with one or more therapeutic modes of action have long been suggested as disease modifying therapies for its treatment. In this study, novel 1-hydroxypyrazin-2(1H)-one iron chelators were synthesized and their physicochemical properties, iron chelation abilities, antioxidant capacities and neuroprotective effects in a cell culture model of Parkinson's disease were evaluated. Physicochemical properties (log ß, log D7.4, pL0.5) suggest that these ligands have a poorer ability to penetrate cell membranes and form weaker iron complexes than the closely related 1-hydroxypyridin-2(1H)-ones. Despite this, we show that levels of neuroprotection provided by these ligands against the catecholaminergic neurotoxin 6-hydroxydopamine in vitro were comparable to those seen previously with the 1-hydroxypyridin-2(1H)-ones and the clinically used iron chelator Deferiprone, with two of the ligands restoring cell viability to ≥89% compared to controls. Two of the ligands were endowed with additional phenol moieties in an attempt to derive multifunctional chelators with dual iron chelation/antioxidant activity. However, levels of neuroprotection with these ligands were no greater than ligands lacking this moiety, suggesting the neuroprotective properties of these ligands are due primarily to chelation and passivation of intracellular labile iron, preventing the generation of free radicals and reactive oxygen species that otherwise lead to the neuronal cell death seen in Parkinson's disease.

Salpyran: A Cu(II) Selective Chelator with Therapeutic Potential.

We report the rational design of a tunable Cu(II) chelating scaffold, 2-(((2-((pyridin-2-ylmethyl)amino)ethyl)amino)methyl)phenol, Salpyran (HL). This tetradentate ligand is predicated to have suitable permeation, has an extremely high affinity for Cu compared to clioquinol (pCu7.4 = 10.65 vs 5.91), and exhibits excellent selectivity for Cu(II) over Zn(II) in aqueous media. Solid and solution studies corroborate the formation of a stable [Cu(II)L]+ monocationic species at physiological pH values (7.4). Its action as an antioxidant was tested in ascorbate, tau, and human prion protein assays, which reveal that Salpyran prevents the formation of reactive oxygen species from the binary Cu(II)/H2O2 system, demonstrating its potential use as a therapeutic small molecule metal chelator.

Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297-391) Intermediates.

The self-assembly of tau into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs) is a significant event in Alzheimer's disease (AD) pathogenesis. Numerous post-translational modifications enhance or inhibit tau assembly into NFTs. Oxidative stress, which accompanies AD, induces multiple post-translational modifications in proteins, including the formation of dityrosine (DiY) cross-links. Previous studies have revealed that metal-catalysed oxidation (MCO) using Cu2+ and H2O2 leads to the formation of DiY cross-links in two misfolding proteins, Aß and α-synuclein, associated with AD and Parkinson's disease respectively. The effect of MCO on tau remains unknown. Here, we examined the effect of MCO and ultra-violet oxidation to study the influence of DiY cross-linking on the self-assembly of the PHF-core tau fragment. We report that DiY cross-linking facilitates tau assembly into tau oligomers that fail to bind thioflavin S, lack ß-sheet structure and prevents their elongation into filaments. At a higher concentration, Cu2+ (without H2O2) also facilitates the formation of these tau oligomers. The DiY cross-linked tau oligomers do not cause cell death. Our findings suggest that DiY cross-linking of pre-assembled tau promotes the formation of soluble tau oligomers that show no acute impact on cell viability.

Nucleation-dependent Aggregation Kinetics of Yeast Sup35 Fragment GNNQQNY.

An N-terminal hepta-peptide sequence of yeast prion protein Sup35 with the sequence GNNQQNY is widely used as a model system for amyloid fibril formation. In this study, we used a reproducible solubilisation protocol that allows the generation of a homogenous monomeric solution of GNNQQNY to uncover the molecular details of its self-assembly mechanism. The aggregation kinetics data show that the GNNQQNY sequence follows nucleation-dependent aggregation kinetics with a critical nucleus of size ~7 monomers and that the efficiency of nucleation were found to be inversely related to the reaction temperature. The nucleus reduces the thermodynamic energy barrier by acting as a template for further self-assembly and results in highly ordered amyloid fibrils. The fibers grown at different temperatures showed similar Thioflavin T fluorescence, Congo-red binding and ß-sheet rich structures displaying a characteristic cross-ß diffraction pattern. These aggregates also share morphological and structural identity with those reported earlier. The mature GNNQQNY fibers did not exert significant oxidative stress or cytotoxicity upon incubating with differentiated SHSY5Y cells. To our knowledge, this is the first study to experimentally validate previous nucleus size predictions based on theoretical and molecular dynamics simulations. These findings provide the basis for understanding the kinetics and thermodynamics of amyloid nucleation and elongation of amyloidogenic proteins/peptides associated with many systemic and neurodegenerative diseases.

Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target.

Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders. Cryo-electron microscopy has recently provided a series of structures for the core of the filaments purified from brain tissue from patients with different tauopathies and revealed that they share a common core region, while differing in their specific conformation. This structurally resolvable part of the core is contained within a proteolytically stable core region from the repeat domain initially isolated from AD tau filaments. Tau has recently become an important target for therapy. Recent work has suggested that the prevention of tau self-assembly may be effective in slowing the progression of Alzheimer's disease and other tauopathies. Here we review the work that explores the importance of tau filament structures and tau self-assembly mechanisms, as well as examining model systems that permit the exploration of the mode of action of potential inhibitors.

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-ß Intermediates Revealing that Self-Assembly Is Required for Aß-Induced Cytotoxicity.

Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-ß (Aß) forms DiY in vitro and DiY-cross-linked Aß is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of Aß42 results in an increase in DiY cross-links. Using DiY as a marker of oxidation, we compare the self-assembly propensity and DiY cross-link formation for a non-assembly competent variant of Aß42 (vAß) with wild-type Aß42. Oxidation results in the formation of trapped wild-type Aß assemblies with increased DiY cross-links that are unable to elongate further. Assembly-incompetent vAß and trapped Aß assemblies are non-toxic to neuroblastoma cells at all stages of self-assembly, in contrast to oligomeric, non-cross-linked Aß. These findings point to a mechanism of toxicity that necessitates dynamic self-assembly whereby trapped Aß assemblies and assembly-incompetent variant Aß are unable to result in cell death.

Internalisation and toxicity of amyloid-ß 1-42 are influenced by its conformation and assembly state rather than size.

Amyloid fibrils found in plaques in Alzheimer's disease (AD) brains are composed of amyloid-ß peptides. Oligomeric amyloid-ß 1-42 (Aß42) is thought to play a critical role in neurodegeneration in AD. Here, we determine how size and conformation affect neurotoxicity and internalisation of Aß42 assemblies using biophysical methods, immunoblotting, toxicity assays and live-cell imaging. We report significant cytotoxicity of Aß42 oligomers and their internalisation into neurons. In contrast, Aß42 fibrils show reduced internalisation and no toxicity. Sonicating Aß42 fibrils generates species similar in size to oligomers but remains nontoxic. The results suggest that Aß42 oligomers have unique properties that underlie their neurotoxic potential. Furthermore, we show that incubating cells with Aß42 oligomers for 24 h is sufficient to trigger irreversible neurotoxicity.

TReND in Africa: Toward a Truly Global (Neuro)science Community.

TReND is a volunteer-scientist run charity dedicated to promoting research and education on the African continent. Focusing on neuroscience, we discuss approaches to address some of the factors that currently stifle Africa's scientific development and our experience in implementing them.

African neuroscience on the global stage: Nigeria as a model.

Of the 572 neuroscience-related studies published in Nigerian from 1996 to 2017, <5% used state-of-the-art techniques, none used transgenic models, and only one study was published in a top-tier journal.