NIHRDataInsights/HRCSData huggingface dataset:
Title: The microbiome and its influence on cognition, brain health and neurodegeneration
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Increased life expectancy in many societies has contributed to the growing social and financial burden of dementia diseases. The aetiology of many of these diseases is unknown, but there is strong evidence that gene-environment interactions play important roles. Evidence suggests that environmental factors such as diet1, physical activity, stress, sleep deprivation2, obesity3 and other lifestyle factors impact on cognitive deterioration. Analytical platforms for deep phenotyping of biofluids such as plasma, urine and CSF based on nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) can generate metabolic “fingerprints” that contain latent information relating to physiological or pathological status, informing on disease mechanisms, diagnosis and prognosis. This technology has been applied to various preclinical and clinical studies of neurodegenerative diseases such as Alzheimers Disease (AD) Huntington’s Disease and vascular dementia. Specifically, metabolic profiling studies on AD and other dementias4,5 have highlighted alterations in a variety of biochemical pathways, including those involving nucleotides, tricarboxylic acid cycle intermediates, energy transfer substrates, carbohydrates, neurotransmitters, phospholipids and amino acids using gas chromatography–MS (GC-MS)6, NMR spectroscopy7 and liquidchromatography- MS (UPLC-MS)8. However, to date, metabolomic studies on dementias have focused on patients with fully developed mild cognitive impairment (MCI) and have been limited to small study groups or, in the case of animal models, only partially reflect disease phenotype. Thus further validation of proposed biomarkers in large cohort studies of prodromal rather than incident dementia is critical to promote mechanistic understanding of the pathological processes and to validate biomarkers for disease risk.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Exploring glial-neuronal interactions at the transition from brain vulnerability to pathology
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Glial activation is associated with the earliest neuronal dysfunction in models of neurodegenerative disease and in human disease post mortem (1). Some of these changes are maladaptive, contributing to network dysfunction. For example, microglial activation is associated with excessive synaptic stripping (2), changes in excitation-inhibition balance, increased microcircuit excitability and early neuronal network dysfunction (3). Pro-inflammatory activated microglia induce a subtype of reactive astrocytes likely contributing to neuronal death in neurodegenerative disorders (4). However, glia also have important homeostatic and neuroprotective roles (3, 5). The complex phenotypes of glial cells, their interactions, and temporal evolution thus need to be understood to discover ways of modulating biasing them towards neuroprotective phenotypes. Microglia play a central role in coordinating homeostatic responses of the glial unit to integrated environmental and neuronal signals, e.g., for balancing amyloid clearance with neuronal activity in the healthy brain (6, 7). Microglial proliferation and activation are amongst the earliest changes in the progression of neurodegenerative pathologies associated with amyloid (and in other neurodegenerative contexts). Understanding microglial homeostatic mechanisms and their failure will provide both insights into neurodegenerative mechanisms and novel concepts for slowing or reversing early disease. My group has been applying a range of imaging, genomic and chemical methods to address homeostatic roles of microglia in the inflammatory neurodegenerative processes of multiple sclerosis and in normal aging (e.g., (8-11)). Methodological advances and a unique cluster of expertise in my group and with close collaborators at Imperial puts us in an ideal position to re-address fundamental questions: • What molecular changes in microglia are associated with early neuronal network homeostasis and • dysfunction in amyloid models? • What chemical signals between glia and neurons mediate this? • How does neuronal activity change the microglial phenotype (and vice versa)? • We have extensively employed in vivo imaging, which has highlighted the dynamics


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of sleep in protecting against amyloid and glial pathology in dementia
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Evidence is building that sleep disturbances in healthy people, repeated over years, might trigger or accelerate pathological processes leading to dementia, e.g. by causing oxidative stress or enhancing amyloid deposition1-5. In healthy middle-aged men, for example, one night of total sleep deprivation produced elevated morning amyloid beta (A42) in cerebrospinal fluid (CSF)6. Sleep deprivation over two months of AβPP/PS1 mice caused them to have irreversibly increased amyloid production and more plaques in cortex and hippocampus and elevated neuronal mitochondrial damage and apoptosis6. Sleep restriction (6 hrs/day for 6 weeks) of 3xTg mice elevated amyloid and pTau in neocortex7; milder sleep restriction of the same strain (4 hours per day for 8 weeks) increased the amount of insoluble tau, and decreased the level of synaptic markers (PSD95)8. Once amyloid pathology has formed in the NREMgenerating areas of the prefrontal cortex, the area of cortex that is responsible for generating delta waves, this could further disrupt NREM sleep, leading to a vicious cycle of sleep disruption and more amyloid deposition9.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Developing novel bioelectronics technologies to modulate neurons and glia in the study of sleep, neuroprotection and cognition
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. A growing body of evidence suggests that aberrant network activity plays a critical role in the progression of neurodegenerative diseases, not just by disrupting the spatiotemporal framework that underpins cognitive or motoric functionality, but also by dysregulating activity of processes in both glia and neurons1–4. Here we will focus initially on Alzheimer’s disease (AD). In addition to their direct effects, network dynamics contribute to the distribution of AD pathology across different brain regions, by propagating a local abnormal elevation of neural activity to regions that are functionally connected2,5. The underlying mechanisms that leads to aberrant network activity in AD and the relationship between an aberrant network activity and the amyloid-β (Aβ) cascade are poorly understood. Their elucidation promises new insights into pathophysiological mechanisms, potential approaches to their experimental control and possible new approaches to treatment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of micro-circuit home
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Understanding the molecular and synaptic events that occur in the earliest stages of Alzheimer’s Disease (AD) offers the greatest hope of identifying novel targets that may lead to treatment1. Destabilised spontaneous activity is one of the earliest signs of pathology in AD2,3 and is predicted to trigger aberrant molecular cascades, impair the function of neural networks and drive synapse loss4,5. My group investigates the synaptic and molecular processes that cause the emergence of destabilised spontaneous activity in both the aged brain and mice that model certain features of AD. We use this knowledge to identify novel targets for intervention. We then ask if we can refine or test approaches that may allow us to positively intervene and either stabilise network activity or prevent emergence of destabilisation. To address these issues we focus on key homeostatic plasticity processes which are known to stabilise activity levels in the healthy brain6–8.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Circadian dysfunction in the e
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Circadian clocks optimize behaviour and physiology by anticipating predictable variations of the environment elicited by the solar cycle. Most notably sleep/wake cycles, cognitive performance, metabolic functions and inflammatory responses are under tight clock regulation. Chronic challenge to the circadian system arising from both genetic make-up and environmental stress (such as shift work, prolonged exposure to artificial light) may lead to severe, age-associated systemic conditions, including diabetes, cardiovascular diseases and Alzheimer’s disease (AD) (1, 2). Although circadian and sleep disturbances are strongly associated with preclinical AD pathology (3, 4), the mechanisms driving such dysfunction in the early stages of the disease are unknown. My group investigates the molecular and circuit mechanisms responsible for the internal coordination of body clocks (5, 6) and the role of glial- neuronal interplay in supporting circadian brain function (7–9). Our working hypothesis is that genetic or idiopathic disease initiation compromises sleep/ circadian function, which further exacerbates neural dysfunction, spiralling disease progression. The main goals of our research programme are: 1) to define the genetically and environmental mechanisms driving circadian dysfunction in the early stages of AD; 2) to identify the cellular and molecular players promoting daily brain homeostasis/plasticity; 3) to exploit these newly identified pathways to potentiate circadian and sleep function, with the aim of preventing and/or delaying disease onset in AD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: Proteostatic mechanisms in FTD and ALS
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders that appear as distinct clinical phenotypes but can share a common genetic aetiology and molecular pathology. TDP-43 aggregates are the hallmark pathology in 95% of all ALS and tau-negative FTD cases, affecting predominantly motor neurons in the spinal cord, brainstem, and motor cortex in ALS and neurons in the frontal and temporal lobes in FTD. TDP-43 is a DNA and RNA binding protein that regulates RNA transcription, splicing, trafficking and translation. Knock-down and overexpression of TDP-43 are both neurotoxic. Mutations in >14 genes account for ~40-60% of familial and ~10% of sporadic ALS and FTD cases. Most gene mutations contribute to the aggregation of TDP-43 in the cytoplasm and/or depletion of TDP-43 in the nucleus. Our discovery that mutations in the gene encoding TDP-43 are neurotoxic confirmed that TDP-43 aggregation/depletion is the primary disease mechanism and that prevention of aggregation and the clearance of aggregates is a major therapeutic target1.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Understanding the role of RNA in the molecular mechanisms of FTD/ALS
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Increasing evidence suggests that RNA plays an active role in a number of neurodegenerative diseases, either directly through the sequestration of RNA binding proteins bound to RNA foci or indirectly through aberrant RNA processing caused by the aggregation of RNA binding proteins1. It has been shown for instance that in myotonic dystrophy, multiple ataxias and Huntington’s disease, primary transcripts containing expanded trinucleotide regions form intranuclear foci that sequester and inactivate key RNA processing proteins. RNA/protein interactions facilitate the conversion of the α-rich prion protein (PrPC) into its infectious β-rich insoluble form (PrPSc) in Creutzfeldt-Jakob disease. In Alzheimer’s disease, translation of aggregation-prone proteins is regulated by iron-dependent ribonucleo-protein interactions. The most striking examples are frontotemporal dementia (FTD) and of amyotrophic lateral sclerosis (ALS) where TDP-43 and FUS mislocalize and aggregate. Both are RNA binding proteins involved in regulating RNA transcription, splicing, stabilization, transport and translation2. RNA-binding protein sequestration (bound to RNA foci or into oligomers) potentially affects the processing of a large number of different RNA molecules leading to the dysfunction of multiple cellular processes, which leads to neuronal cell death. Several proteins involved in neurodegenerative diseases have also been shown to interact with their own cognate mRNAs in an important self-regulatory mechanism that controls translation through a negative feedback loop: when protein concentration is high, binding to the transcript inhibits translation through an editing event that initiates nonsense mediated decay, thus reducing protein levels. A dual role of RNA in function and disease well agrees with the concept that aggregation is a competing pathway to normal function, as we observed for members of the family of polyglutamine proteins associated with spinocerebellar ataxias3. These observations directly suggest that the natural partners of a protein are the best candidates to compete out pathological aggregation and may represent a powerful strategy to design disease-specific molecules which may emulate the natural partners and that could be used as therapeutic lead compounds.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Synapse weakening in the patho
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. The pathophysiology of Alzheimer’s disease (AD) involves the weakening of synaptic connections and ultimately their elimination, which is thought to correlate with disease progression and severity. This positions synapse weakening as an early and pivotal point in AD pathogenesis and an important therapeutic target. Changes to the synaptic expression of AMPA receptors (AMPAR) are considered a major component of synaptic plasticity and connectivity, which are severely dysregulated by disease. Evidence suggests that synaptic dysfunction and aberrant decomposition of dendritic spines occurs prior to Aβ/Tau plaque and tangle formation. The focus of this programme is to explore the role of AMPAR endocytosis in synaptic dysfunction and its contribution to neurodegeneration. We have previously shown that the caspase-3  Akt1  glycogen synthase kinase-3 beta (GSK-3β)  phosphorylation of tau (pTau) cascade is involved in Aβ-mediated pathophysiological synaptic dysfunction in the hippocampus. Therefore, we hypothesise that synapse loss in disease is underpinned by the aberrant activation of synapse weakening signalling cascades. During this programme, we seek to address three specific questions: 1) Which factors modulate the cellular and molecular mechanisms of ‘synapse weakening’ by AD-associated pathophysiology? 2) What are the effects of neuronal activity on the pathophysiology of synapse weakening, and what are the impacts on synapse health? 3) Which synapse weakening molecules and markers are prevalent in AD brain tissue?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Altered RNA metabolism in neur
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. A wide variety of neurodegenerative diseases are caused by mutations in RNA binding proteins. However, the pathogenic mechanisms leading to these disorders are not yet well understood. We study the FUS gene (Fused in Sarcoma), which encodes a conserved RNA-binding protein. Mutations in this gene can lead to the development of Amyotrophic Lateral Sclerosis (ALS), the most common motor neuron (MN) disease in human adults. While FUS is a nucleocytoplasmic shuttling protein, it is mainly nuclear at steady state. Most ALS-associated FUS mutations disrupt the nuclear localization signal (NLS), leading to nuclear exclusion and cytoplasmic FUS aggregates in neurons and glial cells of these ALS patients. FUS is also a major protein component in pathologic cytoplasmic inclusions in some cases of Frontotemporal Lobar Degeneration (FTLD-FUS). However, unlike for FUS-linked ALS, the molecular cause for cytoplasmic mislocalisation in FUS-linked FTLD is unknown and no vertebrate model for FTLD-FUS is available. Therefore, the potential pathomechanisms in FUS-linked FTLD will have to be inferred from the insights from FUS-linked ALS models and its physiological functions. FUS functions in several processes required for proper gene expression, such as transcription, pre-mRNA splicing, and miRNA processing. However, its precise role in these processes and most of its targeted RNAs are, as of yet, unknown. The combination of this lack of knowledge with the lack of FTLD-FUS models has led me and my research group to the conviction that understanding the biological function(s) of normal FUS will be one of the keys to gain insight into the role of FUS-associated neurodegeneration. Furthermore, this will allow us to fully interpret our results from our parallel investigation on the pathomechanisms of FUS-linked ALS using in vitro and in vivo models of disease. The results of our research are expected to reveal the molecular mechanisms implicated FUS-associated ALS and FTLD and identify targets for the development of therapeutic approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The cause and effect of SOD1 destabilization on motor neuron disease
Funder: Medical Research Foundation

Abstract: Superoxide dismutase-1 (SOD1) mutations are destabilizing, inhibit the normal maturation pathway and promote oligomerization into high molecular weight aggregates. This process is toxic, contagious and fatal for motor neurons. We have experimental evidence that immature SOD1 sequesters the copper chaperone for SOD1 (hCCS) thereby inhibiting maturation of newly translated SOD1. Mutants of SOD1 are thought to have compromised zinc binding therefore we hypothesize: compromised zinc-binding leads to hCCS sequestration and accumulation of immature SOD1. The work detailed here will answer the question: why do SOD1 mutations inhibit maturation and what are their structural consequences? We will 1) determine the affinity of SOD1 mutants for zinc, 2) discover the mechanism of disulphide bond transfer to SOD1, 3) detail the reason this disulphide-bond-transfer reaction is ineffective for mutants and 4) describe the pathogenic structures of immature SOD1. This work will give us a complete understanding of the molecular pathology of SOD1 in motor neuron disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: PhD studentship to support structural studies research on AMPA receptor synaptic anchorage complexes
Funder: Medical Research Foundation

Abstract: PhD studentship to support structural studies research on AMPA receptor synaptic anchorage complexes with Dr Ingo Greger and Dr Radu Aricescu at the MRC Laboratory of Molecular Biology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Running assays needed for safely administering and monitoring the biological effects of PRN100.
Funder: Medical Research Foundation

Abstract: The rapidly progressive nature of Creutzfeldt-Jakob disease enables us to test drugs rapidly and efficiently. Sporadic CJD remains a disease with worldwide distribution and accounts for about 1 in 5000 deaths in the UK; apparent incidence continues to increase perhaps reflecting improving ascertainment with around 120 new cases per annum. The MRC Unit has now produced a fully humanised anti-PrP monoclonal antibody (PRN100). A range of preclinical efficacy, pharmacokinetic and safety studies with PRN100 in mice and cynomolgus monkeys have been completed. We have demonstrated in vitro and in vivo proof of principle of a monoclonal (mAb)-based approach to prion disease therapeutics. mAbs that recognise the normal form of the prion protein readily cure prion-infected neuronal cell cultures, removing the substrate for prion propagation, and have potent disease-modifying activity in several animal models of prion disease. The murine parent of our clinical candidate has sub-nanomolar affinity for prion protein, shows marked efficacy in prion-infected mice and can extend survival from <200 days to natural lifespan (>600 days), with these long surviving mice showing no evidence of residual prion infection at autopsy. Studies with the clinical candidate drug, PRN100, in the same preclinical model indicate that it has similar efficacy in vivo.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL