NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigation into the impact of systemic inflammation due to infection on microglial phenotype and its contribution to Alzheimer’s disease neuropathology
Funder: Alzheimer's Research UK

Abstract: When we have an infection, we feel sick and uninterested in things. This is known as “sickness behaviour” and is transitory. Studies have shown that this occurs because certain brain cells (microglia) are switched on by inflammatory chemicals produced during the infection.In Alzheimer’s disease (AD), the microglia are already switched on by the disease, and animal models of dementia have shown that infection modifies microglia to be more aggressive, adding to the brain damage.We propose that common infections (e.g. urinary or lung infections) play an important role in accelerating AD. Using human post-mortem brain tissue from people who died either with or without an infection, both non-demented and AD people, we will investigate whether:(i) Infection has a more marked effect on microglia in AD.(ii) APOE ε4, the main genetic risk factor for AD, modulates the damaging response.(iii) Microglia switched on by infection add to the brain damage in AD.(iv) Infection is associated with the presence in the brain of other inflammatory cells (T-lymphocytes) which may accelerate the disease.This concept has readily applicable implications, suggesting that prevention and management of episodes of infection in the elderly population may slow the progression of dementia.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A cell surface, lipid raft-based signalling complex links amyloid-beta to tau via Fyn
Funder: Alzheimer's Research UK

Abstract: Alzheimer’s disease is characterised by a build-up of amyloid protein in the brain, which clumps together to form toxic aggregates. These aggregates latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface. One of the key cell surface proteins involved in binding amyloid is the prion protein. Binding of amyloid to the prion protein causes activation of signaling pathways in the neurons and ultimately the modification of another key protein tau. These changes cause the nerve cells to malfunction and eventually die. We have evidence that to function in this way the prion protein has to be located in particular regions (so called lipid rafts) at the cell surface that are rich in cholesterol. Removing the cholesterol disrupts the binding of amyloid to the prion protein and the subsequent signaling pathways in the cell. We hypothesise that a cell surface, lipid raft-based signaling complex is key to the binding of amyloid and the subsequent cellular responses, that the prion protein and another protein that we have identified (LRP1) are key structural and functional components of this complex, and that this complex is altered in Alzheimer’s disease and in aging.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Live cell tracking of amyloidogenic species related to Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: In our group, we have recently developed a new kind of microscope, a so called optical super-resolution microscope, which is so powerful that it is capable of visualising the shape of amyloid protein aggregates directly in cultured brain cells, which we use as model systems of disease. We were the first researchers to demonstrate that it is possible to obtain ‘images’ of toxic protein shapes in neurones, and here we propose to use this newly developed tool to shed new light on the mechanisms that lead to the onset and propagation of neurodegenerative diseases. The aims of our proposed research project are: 1) to identify specific species of Aβ and tau in neurones and other cells present in the brain and to relate the shape, and size of these species to the appearance of disease symptoms 2) to study Aβ and tau trafficking in and out of cells and to infer on the implications of this on the possible mechanisms of disease progression. 3) to see whether potential inhibitors of protein aggregation and propagation have an effect on what we observe within the cells we study. We will test several promising anti-aggregation and anti-propagation compounds that our collaborators provide.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mechanisms of neurodegeneration in an animal model of cerebral hypofusion
Funder: Alzheimer's Research UK

Abstract: Over the past decade in Newcastle, we have contributed to the understanding of risk factors for vascular disease and the causes of dementia through multidisciplinary studies in prospectively assessed clinical cohorts but that knowledge now needs to be translated to understand mechanisms and interventions that are effective. To simulate such studies in the elderly, we will implement widely acceptable but highly relevant experimental animal (rodent) model work in collaboration with our colleagues in Edinburgh. We propose to study the long term consequences of low brain perfusion (hypoperfusion) in novel transgenic mice models, which relate to the development of Alzheimer’s disease. We will use state-of-the-art tools to monitor synaptic/neuronal and blood microvessel function and cognitive ability. More importantly, we will assess how neurodegenerative or vascular alterations are ameliorated by two readily implemented interventions including the use of a trial-tested vascoactive compound cilostazol and exposure to physical activity in an enriched environment. The collaboration between our two centres and support from world leaders in transgenic mice model work affords us an unique opportunity to combine expertise to tackle a key understudied area of dementia research. Our strategy will also enable future translation of clinicopathological findings for effective prevention and treatment of dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The ARUK supplement for the JPND funded PERADES consortium
Funder: Alzheimer's Research UK

Abstract: The PERADES Programme (Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease, using multiple powerful cohorts, focussed Epigenetics and Stem cell metabolomics) will find new susceptibility genes for early or late onset Alzheimer’s disease. It will take all genetic findings and test for relationships with lifestyle/environmental factors, using the largest ever sample of epidemiological cohorts, comprising over 500,000 individuals from around the world. Researchers from eleven countries will take part in the study, led by Professor Julie Williams CBE of the MRC CNGG Centre at Cardiff University, UK, alongside group leaders Professor Cornelia van Duijn, Dr Jean-Charles Lambert, Dr Dominique Campion, Professor John van Swieten and Professor John Hardy. Exploiting new statistical approaches to genetic data, researchers will calculate polygenic risk scores, used to identify individuals at both high and low risk of developing Alzheimer’s disease. The will also examine risk profiles in potential pathways to the disease, including immunity. PERADES will pave the way for the development of preventative therapies, and identify new biomarkers of the disease in its earliest phases. It will also explore epigenetic contributions to disease and produce stem-cell resources from individuals with specific risk profiles, for use by the wider scientific community.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Evaluation of tau aggregation detected by novel tau tracer, [18F]T807 PET in mild cognitive impairment subjects: a preliminary collaborative PET study.
Funder: Alzheimer's Research UK

Abstract: Alzheimer’s disease (AD) is characterised by the presence of aggregated “amyloid” and "tau” proteins in the brain associated with inflammation and brain cell damage. Some people with mild memory problems alone (MCI subjects) who have abnormal amyloid deposition can go on to develop AD. These patients may also have evidence of abnormal tau aggregation in their cells. For some years we have been able to image brain amyloid and detect brain inflammation using Positron Emission Tomography (PET). In the last two years, novel imaging agents have been developed to detect aggregated tau protein in the brain. We now propose to investigate the relationship between the presence of abnormal amyloid and tau deposition in the brain and levels of inflammation in AD and MCI subjects and healthy controls using PET scanning. We will also be able to determine whether brain inflammation, amyloid deposition, or abnormal tau formation happens first in MCI subjects. This will reveal underlying disease mechanisms in AD, and increase our understanding of whether brain inflammation causes abnormal tau formation or whether neuroinflammation is secondary to abnormal tau formation. This will form the basis of future treatment decisions using anti-microglial and anti-tau agents in treatment of this disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Automated subcortical brain segmentation using multispectral MRI for improved AD diagnosis and disease tracking
Funder: Alzheimer's Research UK

Abstract: One of the earliest changes in the brains of people with Alzheimer’s disease (AD) is the shrinking of a structure called the hippocampus. This shrinkage can be measured using magnetic resonance imaging (MRI). Using standard MRI you can see some of the boundaries of some structures clearly (like the hippocampus) but other structures are harder to see because they appear similarly bright to neighbouring structures. This makes measuring their size challenging. Different kinds of MRI scan can be taken however, which give complimentary information about the brain structure and health of the tissue. This project aims to combine information from multiple MRI scan types for better visualization of boundaries of brain structures known to be affected in AD allowing for more accurate measurements of size in those structures. The added value of the shape of structures and their tissue health over and above sizes will also be assessed, maximising the amount of information extracted from the scans. This is important as it will allow us to better understand how AD affects different brain structures over time, may aid with diagnosis using non-invasive techniques and may be useful for measuring the effect of AD treatments.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Endoplasmic reticulum-mitochondria interactions and Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: A wide number of cellular functions are perturbed in Alzheimer’s disease but it is not clear how so many apparently disparate functions are all damaged together. Recently, several studies have highlighted how damage to one particular cellular feature termed the endoplasmic reticulum (ER)-mitochondria axis might precipitate many Alzheimer’s disease type changes. ER and mitochondria are two structures within brain cells that perform different functions; ER is involved in making proteins and lipids, and mitochondria generate the energy for the cell. However, their proper functioning requires that they communicate with each other and this involves tethers that physically connect the two structures. In Alzheimer’s disease and related dementias, we and others have shown that ER-mitochondria communication is disrupted. Moreover, we have identified some of the protein tethers that connect ER with mitochondria and have shown that these are damaged in some forms of dementia. This project is to continue these studies. We aim to determine how the tethers and ER-mitochondria interactions are damaged in Alzheimer’s disease and to identify lead compounds that might correct this damage. We believe that our studies may reveal a new therapeutic target for treating Alzheimer’s disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Fe65/APP signalling and brain-derived neurotrophic factor in Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: The amyloid precursor protein (APP) is strongly linked to Alzheimer’s disease. This is principally because it is cleaved by enzymes to produce amyloid beta peptide (Abeta) that is deposited in Alzheimer’s disease brains. However, cleavage of APP to produce Abeta is likely to change APP function and this may also contribute to Alzheimer’s disease. One function of APP is in nuclear signalling. This is where proteins in cells are moved into the compartment that stores the cells genetic material. Nuclear signalling causes alterations to many processes within cells. This function of APP is mediated by binding to another protein, Fe65. Recently we have found that brain-derived neurotrophic factor (BDNF), a substance produced in the brain induces changes to Fe65 termed phosphorylation. BDNF has been shown to be protective in some Alzheimer’s disease models but its mechanism of action is unclear. This project is to investigate whether BDNF-induced Fe65 phosphorylation influences APP-Fe65 nuclear signaling. As such, it may provide insight into the mechanisms of protection of BDNF and so reveal new therapeutic targets for Alzheimer’s disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Title: Identification of the Alzheimer pre-protein as a potential regulator of endosomal phosphoinositide metabolism; a novel mechanistic pathway to neurodegeneration?
Funder: Alzheimer's Research UK

Abstract: An important feature of Alzheimer's disease is the accumulation of membrane surrounded structures in neurons affected by the disease. These structures (so-called endosomes, lysosomes and autophagosomes) are important for breaking down cellular material, particularly if it is no longer functional. Work in mice has shown that the accumulation of lysosomes and autophagosomes is highly toxic to neurons and may explain why neurons die in the progression of Alzheimer's disease. Why exactly these structures accumulate in Alzheimer’s disease is currently unclear. Very recent work in our lab has shown that the Alzheimer pre-protein (APP), a molecule of key importance in Alzheimer's disease, can bind to a protein complex that modifies the lipid composition of endo- and lysosomes. We believe that this may represent a control mechanism for regulating the lipid composition of endo- and lysosomal membranes. This is of prime importance for the normal break-down of non-functional cellular material in lysosomes and autophagosomes. The proposed project will test the idea that inappropriate processing of APP – as is known to occur in Alzheimer’s disease – leads to impaired regulation of endo- and lysosomal membrane composition with detrimental consequences for cell function and survival.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Modelling hexanucleotide expansion repeats of C9ORF72 in Frontotemporal Dementia
Funder: Alzheimer's Research UK

Abstract: Frontotemporal dementia (FTD) is a devastating disease that runs in almost 50% of all families afflicted with FTD. Research into the molecular basis of disease is fundamental for the development of new therapeutic strategies. Alterations in the gene C9ORF72 were recently identified in a very high percentage of cases and to date represent the most common genetic abnormality in FTD. These genetic alterations are due to aberrant expansion of the C9ORF72 gene which is thought to cause the majority of FTD. However, the underlying mechanisms are not known. Here we propose to use the fruitfly Drosophila to model these C9ORF72 alterations in the fly and to study how they can cause FTD-like disease formation. Because C9ORF72 alterations come together with accumulation of TARDBP/TDP-43, another gene implicated in FTD, and possibly also TAU, we will also use our fly model to investigate the interplay between C9ORF72, TDP-43 and Tau. We expect that our Drosophila model of hexanucleotide expansion repeats of C9ORF72 will determine mechanisms underlying disease formation and progression, which in turn will identify therapeutic targets that can directly guide clinical research and the development of novel strategies for the targeted treatment of C9ORF72-related FTD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigation of the mechanism by which the C9ORF72 intronic repeat expansion causes frontotemporal dementia
Funder: Alzheimer's Research UK

Abstract: The investigation of genetically inherited forms of dementia has provided invaluable insights into the causes of dementia and potential treatments, including highlighting the importance of both Abeta and tau. Very recently the C9ORF72 gene has been identified as the most common genetic cause of frontotemporal dementia and of motor neuron disease. Therefore, identifying how this gene causes neuronal death should reveal important new insights into the causes of dementia and other neurodegenerative diseases. Currently nothing is known about how C9ORF72 causes neurons to die, but the mutation in the C9ORF72 gene is similar to mutations in other neurological disease genes that lead to alterations in the cell’s RNA. We therefore plan to characterise RNA from cells and brains of people with C9ORF72 mutations, as the UCL Institute of Neurology has identified a large number of people with C9ORF72 mutations and has a wide range of samples donated for research purposes. These studies are likely to give new insight into how the mutation leads to dementia and may identify new therapeutic avenues.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Differential production of amyloid-beta from the APP isoforms
Funder: Alzheimer's Research UK

Abstract: The neurotoxic amyloid-β peptide is cut out of the larger amyloid precursor protein (APP) by enzymes called secretases. In the brain there are three main forms of APP which differ in the number of amino acids they contain – APP695, APP751 and APP770. Recently, we have shown that amyloid-β is preferentially produced from APP695. However, the mechanism underlying this differential production of amyloid-β from the three forms of APP is not clear. In this proposal we aim to determine whether the localisation of APP in different regions of the cell through specific interaction with another protein accounts for this differential processing. We will also determine the relative amounts of the three forms of APP in the human brain both in Alzheimer’s disease and in aging, and investigate whether the forms of APP differently protect cells against oxidative insult. The information gained from this work will provide a more complete picture of the cellular mechanisms involved in the production of amyloid-β from APP and may identify new targets for the treatment of Alzheimer’s disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Impaired Tight Junction Protein Signalling in Astrocytes In Alzheimer's Disease
Funder: Alzheimer's Research UK

Abstract: Astrocytes are star-shaped cells that have important functions, including supporting and regulating transmission between brain cells (neurons), and controlling the extracellular environment. Astrocytes show injury with progression of Alzheimers disease (AD), suggesting that loss of normal astrocyte function contributes to impaired neuron function. Using methods to specifically study changes in the genes that are expressed by astrocytes, we have recently found that astrocytes show reduced expression of a class of genes for tight junction proteins (TJP) with AD progression. TJP are important in controlling the movement of substances across blood vessel walls into the brain, but there is evidence from our work and the literature that they are also expressed in astrocytes where they may have other functions, regulating a number of metabolic, so-called signalling, pathways within the cells. This studentship will investigate the role of TJP in astrocytes and in the response to injury and will investigate the idea that reduction of TJP contributes to astrocyte pathology in AD. The project will use human brain-tissue samples and an experimental cell-culture model. Restoring the normal supportive function of astrocytes is an additional therapeutic approach to AD, and understanding the complex processes, such as TJP-signalling is essential to further this ambition.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Altered Heparan Sulfate in Ageing and Dementia: a Potential Axis for Dysregulation of BACE-1 in Alzheimers Disease
Funder: Alzheimer's Research UK

Abstract: Cleavage of amyloid beta-protein precursor (APP) by the enzyme beta-secretase (BACE1) is a key step in Aβ peptide production and accumulation in brain plaques in AD sufferers. We have discovered that a complex cell sugar called heparan sulphate (HS) inhibits BACE1, providing a new drug discovery target and indicating a possible role as a “brake” on Ab generation in the brain. HS is also known to change in human tissues with ageing and in AD brains, and we have new preliminary evidence that certain enzymes involved in making HS in cells are present at lower levels in AD. Our hypothesis is that changes in HS structure during ageing and in dementia may result in taking the “brake” off BACE-1 activity, leading to elevated generation of pathogenic Abeta peptides. We will analyse the structure and BACE-1 inhibitory activity of HS from brains of AD patients and age matched controls, and study expression levels of enzymes which make HS. These studies will help us to understand the in vivo relevance of HS to AD pathogenesis, support targeting HS regulation of BACE1 for development of disease-modifying drugs, and may reveal new genetic or biochemical markers for risk of development of AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Convergence of Abeta and tau pathogenic mechanisms on axonal transport
Funder: Alzheimer's Research UK

Abstract: Normal molecular and cellular mechanisms, and disease mechanisms, often act in pathways where one protein signals to another, activating it, blocking it, changing its location or its expression, etc. Molecular events are considered as ‘upstream’ or ‘downstream’ in these pathways, and pathways can converge. This project seeks to understand the pathways linking Abeta and tau pathology in Alzheimer’s disease. Imagine a car accident where one driver exceeds the speed limit and another fails to look carefully. These actions converge (in this case literally) to cause the accident. If the speeding driver had overslept and the other had been distracted, these events would be 'upstream' of the accident. If the road is blocked making other people late for work, this would be ‘downstream’. In Alzheimer’s disease, tau appears to act downstream of Abeta or on a separate branch of the pathway (like the other driver) that converges on a common, downstream molecular event. New data from our group provide clues about the function of this putative common, downstream target, which we aim to investigate this further and potentially identify the molecule/s involved. This could lead to new strategies to prevent either branch of the pathway from causing disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL