NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterisation of a novel in vivo model of human tauopathy
Funder: Alzheimer's Research UK

Abstract: Animal models are urgently required that accurately represent dementia in humans so that we can study changes in the brain during progression of dementia, and to enable accurate testing of new drugs. Several animal models do exist, but the majority of these are disadvantaged by the fact that they contain unrealistically high amounts of specific proteins (usually amyloid and/or tau), sometimes in parts of the brain where they would not normally be found. In this project we will use a new mouse model we have created that contains normal amounts of a particular form of tau that we identified in human brain. Tau protein is a major component of the tangles that contribute to brain degeneration that occurs in dementia. The tau fragment we identified is associated with disease and forms tangle-like aggregates in cells. Recently we made a new genetically-modified mouse that produces this human tau fragment in the brain. We plan to examine the effects of this tau fragment on the development of dementia, by measuring tau aggregation and examining mouse behaviour in parallel. We hope that the findings from this project will provide a better model for testing new treatments as they become available for dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: NeuroTraffic: Orientated neuronal networks for investigating mechanisms of tau propagation
Funder: Alzheimer's Research UK

Abstract: The brain controls our daily activities, such as seeing, talking and moving, and also our emotions and behaviour. Within the brain, individual nerve cells connect to form large networks that process, propagate and store all the information required to perform these various tasks. Unfortunately, toxic agents such as viruses and bacterial toxins can exploit these nerve cell “highways” to spread throughout the brain. The proposed project addresses if protein aggregates such as tangles, a hall mark of many neurodegenerative diseases, also directly travel along nerve cell networks to spread to other areas of the brain, and if so, what mode of transport they take. To address this question, we will use an innovative microchip that allows direct access to individual connected nerve cells and thus recreates the small nerve cell highways that can be individually tested. We will film, in real-time, the spread of these tangles to understand their movement. This experimental platform will also be useful to screen drugs for their ability to stop traffic of toxic material along nerve cells. A better understanding of how damaging materials move through the brain and enters nerve cells will aid the development of more effective therapies for the treatment of dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Using genetic variability in whole transcriptome expression in the hippocampus and temporal cortex to understand the pathogenesis of Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: In the past two decades scientists have shown that some individuals have common changes in their DNA (the instruction manual for all the building blocks needed to make the body) that put them at higher risk of developing Alzheimer’s disease (AD). Some of these genetic risk factors might cause disease by changing how much or the way particular genes are expressed in the brain. We will check this by measuring the genetic variation an individual carries and linking this information to the genes expressed in the brain. We will use a technology called "RNA-seq" to measure all kinds of gene product from specific brain regions and pure collections of cells. We will focus on brain regions and cell types most affected in AD, such as the hippocampus and temporal cortex, in neurologically normal individuals and people who suffered from AD during their life. We already have the RNA and DNA data we need on normal individuals, which means that the new information we generate will be quickly and cost-effectively analysed so that we can make progress faster. All the data we generate on the human brain will be made publicly available so that other scientists can use this information too.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Hippocampal sclerosis – a poorly understood cause of dementia among the older old
Funder: Alzheimer's Research UK

Abstract: Dementia is a concern for our time, one consequence of the success in extending average human lifespan. One important cause of dementia among the older old may be hippocampal sclerosis - a condition about which very little is known. It is characterized by severe nerve cell loss in the part of the brain controlling memory processing. How this neuron loss develops, what it relates to, and how common hippocampal sclerosis is, remain unclear. This PhD project aims to fill this gap of knowledge by determining the frequency of hippocampal sclerosis occurrence in the population, describing its clinical characteristics identifying whether early diagnosis is possible, assessing genetic predispositions, exploring its relations to other types of dementia pathology, and by analyzing possible biological which trigger its development. This is only feasible in studies which have population representation, including the older old, which have been followed by brain donation and pathological analysis. Three of only seven studies of this kind in the world offer a unique combined collection of almost a thousand brains. Within this PhD project, epidemiological, neuropathological, biochemical and statistical methods will be used to clarify the background of hippocampal sclerosis and its role in dementia in the elderly population.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the effect of ApoE genotype on synaptic dysfunction using sporadic Alzheimer’s disease patient iPSC-derived cells
Funder: Alzheimer's Research UK

Abstract: The majority of Alzheimer’s disease (AD) is sporadic, however the presence of a gene encoding the E4 form of apolipoprotein E (ApoE) has been associated with increased risk of developing the disease. ApoE is primarily produced by astrocytes, which are the supporting cells of the brain and play important roles in regulating how nerve cells (neurons) communicate with one another. A key feature of AD is that the communication between neurons at synaptic connections stops functioning properly. In this project we will take advantage of the latest stem cell technologies to generate both neurons and astrocytes from AD patients with the ApoE4 gene. This will establish a new model of the disease in which we can systematically examine how ApoE affects different aspects of synaptic communication. We will assess how ApoE affects the ability of neurons to form functional synapses and the potential for synapses to undergo changes in strength - a cellular basis of memory that is believed to be compromised in the early stages of AD. Finally, this approach will enable us to test whether synaptic impairments can be prevented by growing patient neurons with astrocytes from healthy individuals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of TREM2 in neurodegeneration
Funder: Alzheimer's Research UK

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. A major known risk factor in late-onset disease is having the ApoE4 gene. Recently another genetic risk factor has been identified called TREM2 and variations in this gene cause susceptibility to late-onset AD with similar odds to the ApoE4 gene. The TREM2 gene encodes a receptor protein on the surface of a subset of brain cells, called microglia. These cells form an important part of the immune response within the brain. TREM2 triggers immune responses when associated with other proteins and is also involved in clearing away damaged tissue, therefore reducing the amount of inflammation. We suggest that the neurodegeneration in TREM2-associated AD is driven by a chronic inflammatory process with dysfunction in microglial cells. We propose to investigate whether carrying a TREM2 mutation alters AD brain tissue by examining the location and distribution of the TREM2 protein in brain; determine how the TREM2 mutations alter inflammatory cell function and investigate the 3D relationship between the pathological proteins found in AD and the microglial architecture. How TREM2 is involved in neurodegeneration remains elusive unravelling the mechanism will lead to a greater potential for therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Molecular mechanisms of C9ORF72 repeat expansion toxicity in frontotemporal dementia
Funder: Alzheimer's Research UK

Abstract: Frontotemporal dementia is the second most prevalent form of early onset dementia after Alzheimer’s disease. A large proportion of frontotemporal dementia cases are caused by a genetic defect that enlarges part of a gene. The aim of this project is to understand how nerve cells from frontotemporal dementia patients handle this defective gene. This knowledge will open the way to the development of treatments to slow down or, hopefully, halt the progression of disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Regulation of microglial proliferation in Alzheimer Disease
Funder: Alzheimer's Research UK

Abstract: There is growing evidence from neuropathology, epidemiology and genetic studies to implicate the innate immune system in the pathogenesis of Alzheimer’s disease (AD). The microglia, the resident macrophages or innate immune cells of the brain, are normally present in small numbers and have a quiescent phenotype. During degeneration of neurons in the brain, however, they become activated in morphology and phenotype and increase in number. We have shown that these activated microglia are further influenced by inflammation in the periphery, such as that associated with common infections. The peripheral inflammation communicates with the brain and can switch the microglia to a phenotype that affects both the function and survival of neurons. We have shown that peripheral infections are associated with an acceleration of cognitive decline and exacerbation of symptoms in individuals with AD. In this project we wish to understand the signals that drive the proliferation of microglia, since their increased number is important in amplifying the detrimental consequences of peripheral inflammation. We will identify the molecules responsible for driving microglia proliferation in tissues samples from both animal models of AD and AD brains. We will use this information to identify potential steps that might inhibit their proliferation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Ultra-high field MRI in early Alzheimer’s disease: characterising iron deposition
Funder: Alzheimer's Research UK

Abstract: Iron is essential for healthy brain function but has also been implicated in the progressive brain damage of Alzheimer’s disease. This project will use advanced MRI brain imaging techniques, performed on a state of the art MRI scanner, to form detailed pictures to map iron in the brain and look at the way this is related to the structure and functional pathways in the brain. It is known that certain areas of the brain have increased iron deposition in Alzheimer’s disease and with highly detailed scanning, provided by our new scanner this can be characterised. Specific regions of the brain have been shown to work together, forming networks. One such network is called the default mode network and this has been found to be altered in Alzheimer’s disease. We will also look at how the iron deposits relate to and interact with the alterations in this network. By gaining greater understanding this may help us find an early iron based MRI marker for detecting and monitoring Alzheimer’s disease as well as providing insights into the effect the disease has on the brain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Differential vulnerability of hippocampal synapses to amyloid beta
Funder: Alzheimer's Research UK

Abstract: A puzzling characteristic of Alzheimer’s disease progression is that one of the earliest symptoms is the inability to lay down new memories, whereas those old memories about events, people and places are preserved until much later in the disease. With this pilot grant we aim to investigate why this occurs. It is increasingly recognised that the connections between neurons, known as synapses, are the substrate for learning and memory. However, even within one type of neuron, there are different types of synapses that may play distinct roles in the brain. Specifically, one type of synapse may be more important for learning, while another acts as a permanent store of memory. We have the experimental tools to target each of these types of synapse in living tissue, and so would like to investigate whether they are differentially vulnerable to the amyloid beta peptides that trigger the synaptic dysfunction thought to underlie the early stages of Alzheimer’s disease. If we find that the synapses important for learning are more affected by toxic amyloid beta peptides, this would potentially explain why the disease progresses as it does, and also enable early treatments to be specifically targeted to protect this type of synapse.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Patient-derived stem cells models for C9ORF72-mediated frontotemporal dementia
Funder: Alzheimer's Research UK

Abstract: Mutations in the C9ORF72 gene have recently been described as a major cause of frontotemporal dementia and it is now a major research challenge to understand how these mutations cause cell death. It is therefore necessary to develop cell models that can be cultured in the laboratory and recapitulate key features of the disease in the same cell type that is affected in patients. We have generated fibroblast (skin cell) lines from 3 patients with the mutation in C9ORF72 and used reprogramming technology to convert these skin cells to stem cells. In this proposal, we will drive our stem cells into the same type of neurons affected in frontotemporal dementia and determine how closely they replicate the changes that occur in patient brain. The outcome of this project will be a physiologically relevant, validated cell model that can be used to explore the causes of cell death linked to C9ORF72 and will also be a suitable model for drug screening.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Hippocampal subregions in early Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: Diagnosing Alzheimer’s disease early, before significant memory loss, will increase the potential benefit of future treatments that slow or halt disease progression. The hippocampus is an area of brain affected early in Alzheimer’s disease, resulting in memory loss. The hippocampus can be seen using Magnetic Resonance Imaging (MRI). International collaborative studies have demonstrated that MRI of hippocampus is a useful way to identify patients with established Alzheimer’s and monitor the effects of treatment. Due to the development of new MRI techniques, we now think it might be possible to look in more detail at hippocampal structure in order to identify patients with very early Alzheimer's disease before significant memory loss occurs . We will scan patients with mild cognitive impairment and mild Alzheimer’s disease and hope to be able to demonstrate the very earliest changes in hippocampus such as change in the shape and characteristic MRI profile of the hippocampal subfields affected in Alzheimer's disease. We will measure the relationship between MRI findings and memory. We expect that as a result of our work we will be able to propose new MRI techniques that will enable early identification of patients likely to develop symptoms of Alzheimer's disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Finding genetic variation in a newly identified Alzheimer’s disease pathway
Funder: Alzheimer's Research UK

Abstract: Alzheimer's disease is a disorder caused by a combination of environmental and genetic factors, but many of these factors are unknown. The information contained in our genes differs between people and by comparing the genes of a group of Alzheimer's disease patients with a group of healthy people we aim to spot different patterns in the information code that may be associated with disease. We have recently identified TREM2 as a new Alzheimer's disease gene and we now aim to study genes that are known to work together with TREM2, because there is a very high probability that these genes will also be involved in the way Alzheimer's disease develops and/or progresses. Identifying differences in these genes will allow us to better understand how the disease starts, since we will have more pieces to construct the complex puzzle that Alzheimer's disease is.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Epigenetic modification of mitochondrial genes in Alzheimer's disease (AD)
Funder: Alzheimer's Research UK

Abstract: Mitochondria, the ‘power-plants’ are of the cell produce energy via a process called the electron transport chain (ETC). Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome (DNA). Of the 97 proteins involved in the ETC, 13 are encoded by genes located in the mitochondria. The ‘expression’ of these genes is very tightly regulated to ensure enough energy is produced to fuel the cells. In Alzheimer’s disease (AD) there appear to be changes in mitochondria, although we are unsure of the exact molecular mechanisms driving this. The expression of genes in the nucleus is regulated by ‘epigenetic’ processes that can turn genes on and off. We have shown that epigenetic changes occur in AD brain implicating these processes in disease. Recently, scientists have shown that DNA methylation, a key epigenetic mark, also regulates genes in the mitochondrial genome. This project will use cutting-edge methodologies to address the hypothesis that mitochondrial dysfunction in AD brain is a result of epigenetic changes to the mitochondrial DNA. Excitingly this project could identify new targets for drug development as epigenetic changes are potentially reversible and epigenome-altering drugs are already in development for treating cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Modulating miRNA within and beyond the brain compartment
Funder: Alzheimer's Research UK

Abstract: Chronic inflammation arising from conditions such as obesity, diabetes and high blood pressure throughout the body are associated with development of Alzheimer’s disease (AD). Long-term inflammation in any organ, including the brain and its blood vessels, can harm cells. Clinical trials that have been designed to reduce inflammation or to reduce cholesterol in patients with AD have not led to any clinical improvements. This suggests that important changes are occurring before AD symptoms appear and any interventions in mid-life are more likely to be beneficial. We need to understand the relevant disease-modifying pathways that link inflammation with AD. Recently, there has been increased interest in understanding whether microRNA (miRNA), small modulatory nucleic acid sequences that regulate cell behaviour, may be associated with onset of AD. Molecular studies have revealed in animals that these miRNAs are altered and associate with degeneration of brain cells. By exploring how miRNAs can influence cell behaviour at the boundary between the blood and brain compartments we will begin to understand how changes in miRNA may lead to AD. This will allow us to understand the importance of miRNA-controlled pathways in brain blood vessels and brain cells during development of AD and to design novel treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Does improved mitochondrial health protect against tauopathy-induced neurodegeneration?
Funder: Alzheimer's Research UK

Abstract: Our ageing society is accompanied by an increase in the number of people diagnosed with Alzheimer’s disease (AD) – a syndrome associated with memory loss. Underpinning this disease is the progressive loss of brain cells (neurons) and despite years of research, prevention or treatment methods are still lacking. One of the culprits causing neuronal loss in AD is a molecule called ‘tau’; in its dysfunctional state, it interferes with cellular transport mechanisms For example mitochondria, the cellular ‘power-stations’, can no longer reach areas of the cell where their energy production is necessary. Tau also interferes directly with mitochondrial function, insufficient energy is produced to sustain neuronal function and cells die. Here, we will assess whether maintenance of mitochondrial function in the face of tau-onslaught can prevent neuronal loss and memory decline. We will use mice with high levels of dysfunctional tau and by increasing a mitochondrial protein that maintains mitochondrial health in times of stress, we are aiming to increase neuronal resilience and life span. In addition to assessing neuronal survival, we will investigate whether tau-mice with improved mitochondrial health perform better in memory tasks. We are hoping to identify novel therapeutic target avenues to support mitochondrial function in AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Imaging copper trafficking in Alzheimer’s disease with PET: potential clinical applications
Funder: Alzheimer's Research UK

Abstract: Growing evidence suggests that a dysregulation of copper (Cu) metabolism occurs in the brains of those with Alzheimer’s disease (AD) and that this dysregulation is a crucial driver of neurodegeneration1. We will use positron emission tomography (PET) to follow radioactive copper (64Cu) in the brain, observing how fast our injected 64Cu radiopharmaceutical enters and exits the brain, and where it accumulates. We will investigate this 64Cu trafficking in an AD mouse model that develops brain plaques and later compare it to age-matched normals. We suspect the brain handles Cu differently in AD patients and this abnormal Cu metabolism may occur before memory deficits arise. In addition to PET, we will use X-rays to see where and how much native copper exists in the same brain tissue that we image with PET. The biodistribution of both 64Cu (observed with PET) and native (observed with X-rays) will be matched with standard measures of AD pathology (plaque deposition and memory scores). This study will indicate whether PET imaging of 64Cu can be used to detect early changes in AD before symptoms become apparent. If successful, this method has potential for immediate clinical translation since our 64Cu radiopharmaceuticals have already been used in man.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL