Nuclear tau and its potential role in Alzheimer’s disease

Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer’s disease (AD). For nearly four decades, research efforts have focused more on tau’s role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau’s localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration

From chromatin to protein synthesis: the role of glutamate, amyloid beta and tau in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia, which is characterised by extracellular Aβ plaques and intracellular neurofibrillary tangles, comprised of fibrils of Aβ42 and tau protein, respectively. A species of tau protein localised to the nucleus has been discovered, but its role in AD is still unclear. Glutamate excitotoxicity, oxidative stress, DNA damage, alteration of the chromatin and nucleolar stress are key features of AD. The early stages of the disease are characterised by minimal neurodegeneration and altered protein synthesis machinery. The culprit (s) and molecular link between these changes and the role of nuclear tau are unclear. This work utilised glutamate stress and Aβ42 oligomers to investigate the involvement of nuclear tau in the chromatin alteration, nucleolar dysfunction, and downstream protein synthesis impairment that occurs in AD. This revealed that glutamate stress in SHSY5Y neuroblastoma cells results in oxidative stress, a nuclear upsurge of phosphorylated tau and delocalisation of nucleolar tau, alongside, DNA damage, heterochromatin loss, nucleolar stress and protein synthesis inhibition, partly through eIF2α phosphorylation. Likewise, short incubation of SHSY5Y cells with Aβ42 oligomers led to significant oxidative stress, with gradual accumulation of nucleolar stress, which resulted in altered transcription and processing of 45S pre-rRNA and decrease in protein synthesis, without DNA damage. Although both glutamate and Aβ ultimately decreased protein synthesis, Aβ incubation led to an increase in heterochromatin formation and a reduction in RNA synthesis without DNA damage, pointing to a different mechanism of toxicity by the Aβ and glutamate stress. To characterise a nuclear role for tau, this work localised tau in the nucleolus and heterochromatin in the SHSY5Y cells and the human brain, where it associates with TIP5 – a key player in heterochromatin formation. Accordingly, tau knockdown destabilises the heterochromatin and increases rDNA transcription, indicating that tau is essential for silencing of the rDNA and heterochromatin stability, similar to TIP5. Overall, this thesis provides evidence that implicates glutamate and Aβ toxicity in some of the changes that occur in the disease and specifically implicates Aβ42 as a key culprit that drives changes in the early stage of the disease. It also reveals a new role for tau in the nucleus and points to its pathological involvement in AD

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

Atypical, non-standard functions of the microtubule associated Tau protein.

Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau's role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer's disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.g. epilepsy, excitotoxicity, and environmental stress. This review will focus on atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplastic and neuropathological implications of Tau in both the central and the peripheral nervous system

African Neuroscience on the Global Stage: Nigeria as a Model

Several challenges contribute to Africa’s trailing position in the global production of knowledge. Decades of focused work through international and local programmes have thus far been unable to lift the continent onto its scientific feet. To learn more about the strengths and weaknesses of neuroscience research carried out on the continent today, that would enable the development of robust programmes focusing on specific needs, a strategy is required to extract information about specific contributions of African laboratories. Nigeria, Africa’s most populous nation, is among the top beneficiaries of international programmes promoting neuroscience research in Africa. Therefore, to establish and test a framework for evaluating neuroscience output from the continent, we here focussed on Nigeria’s neuroscience publications over the past two decades. Using PubMed key-word search and defined exclusion criteria, we extracted 572 neuroscience articles from Nigeria-based laboratories published between 1996 and 2017. Articles were automatically categorised into clinical and epidemiological studies (55.5%) or basic neuroscience (44.5%) using a support vector machine and decision tree algorithm. From here, we extracted each publication’s use of model species, methods, citations received and the publishing journal’s metrics. We find that over the 21 year period surveyed, only one Nigerian-led neuroscience paper was published in a “top-tier” international journal with an impact factor of &gt;8. However, about half (55%) of PubMed indexed articles were published in reputable journals with an impact factor between 1-4. These publications primarily comprised basic (61%), rather than clinical and epidemiological studies (39%) which were instead mostly published in lower-ranking journals. Next, we find a worrying account of model species and research tools employed in Nigerian-based neuroscience. For example, no studies used genetically amenable model systems such as zebrafish, Drosophila, C.elegans, or transgenic mouse strains. Instead, popular model species were human (54%), rat (30%) and wild-type mice (11%). In line, research techniques employed were dominated by “basic” techniques such as Hematoxylin and Eosin stainings or classical behavioural analysis, with only 8% of studies using more modern techniques like PCR, Western blotting or forms of fluorescence microscopy. Perhaps as one consequence, even though medicinal plants have been used to treat diseases for decades by locals, and 41% of basic neuroscience studies investigated their potential utility in treating disease, none made it into local clinical research. Together, these findings highlight two clear access points for the support of Nigerian neuroscience in the future: Investment in the training and infrastructure in the use of more modern research techniques, and the widespread promotion of genetically amenable model species. Moreover, any such effort might consider specifically targeting existing basic over clinical or epidemiological research efforts. In time, it will be important to also assess the neuroscience output across the entire continent

Salpyran: a Cu(II) selective chelator with therapeutic potential

We report the rational design of a tuneable Cu(II) chelating scaffold, 2-(((2-((pyridin-2-ylmethyl)amino)ethyl)amino)methyl)phenol, Salpyran. This tetradentate (3N,1O) ligand is predicated to have suitable permeation, has an extremely high affinity for Cu compared to clioquniol (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)(3N,1O)]+ 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 (ROS) from the binary Cu(II)/H2O2 system demonstrating its potential use as a therapeutic small molecule metal chelator (SMMC)

Science communication practices and trust in information sources amongst Nigerian scientists and journalists

Relatively few studies have explored the communication practices of researchers and journalists working in African contexts. We set out to explore the communication activities undertaken by Nigerian health researchers and journalists, their motivations and the barriers they face in communicating about health topics with lay audiences, as well as their trust in a range of sources of scientific information. The study adopted a survey methodology, recruiting 69 participants at a communications training workshop for both health researchers and journalists. We found high levels of participation in research communication amongst health researchers compared with previous work. While many barriers are similar to those faced by researchers in other contexts, our respondents highlighted that lack of support from managers is a significant hurdle, which has not been highlighted in other studies. Both journalists and researchers primarily communicate science with the aim of educating, informing, entertaining or inspiring their audiences. Regarding trust, both researchers and journalists broadly trust sources linked to science, such as academic journals. However, trust in industry, NGOs and other media was higher amongst journalists than health researchers. Least trust was invested in social media sources, with the exception of material posted on accounts linked to universities

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

Novel avenues of tau research

IntroductionThe pace of innovation has accelerated in virtually every area of tau research in just the past few years.MethodsIn 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.ResultsRepresenting 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.DiscussionThe 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