NIHRDataInsights/HRCSData huggingface dataset:
Title: Phosphorylation of kinesin light chain and calsyntenin-1/alcadein mediated axonal transport and processing of APP in Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: Neurons comprise cell bodies and wire-like processes called axons and dendrites that connect to each other at structures called synapses. There are up to 100 billion neurons and 100 trillion synapses in the human brain and this network enables the computing of information. Most neuronal proteins are made in the cell body and since axons and dendrites require proteins to function, they have to be transported from the cell body into and through the axons and dendrites to the synapse. This transport of protein “cargoes” involves “molecular motors” that run on “rails” and utilize a “fuel” called ATP. One key axonal motor is kinesin which moves along microtubule “rails”. As such, axonal transport is like a train journey with an engine (kinesin) using fuel to move cargoes along rails. We now know that axonal transport goes wrong in Alzheimer’s disease but it is not clear which aspect is defective. Like a train journey, there could be a problem with the engine, fuel supply, rails, signaling or even the cargoes themselves. We have discovered a new signaling pathway that has major implications for defective axonal transport in Alzheimer’s disease. This project is to study further, its role in Alzheimer’s disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: Alzheimer's disease and the auditory world: from symptoms to brain networks
Funder: Alzheimer's Research UK

Abstract: Many patients with Alzheimer's have difficulty making sense of the sound environment in which we all live. Ths can manifest as inability to follow conversations or process information in the presence of background noise, abnormal sensitivity to sound, uncertainty about the source and location of sounds, and altered enjoyment of social situations and music. Besides their implications for the overall quality of patients' lives, these problems may give an early, potentially diagnostic clue to the presence of the disease. However in contrast to memory, vision and other brain functions, the processing of sound in Alzheimer's has been little studied. Here I propose a PhD project to investigate how patients with Alzheimer's analyse the sound world compared with healthy subjects and patients with another dementia (Pick's disease). The brain changes associated with listening to sounds will be compared in volunteer patients with Alzheimer's, patients with Pick's, people at-risk of familial Alzheimer's, and healthy volunteers using specialised MRI brain scanning, psychological and hearing tests. This information will help us understand the nature of the brain malfunction and suggest rational management approaches. In addition it may provide new information relevant to early diagnosis of Alzheimer's in relation to other dementia diseases.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL
Title: Investigating the effect of Fyn tyrosine kinase on intraneuronal trafficking of tau in models of Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: Current drugs for Alzheimer’s disease (AD) do not significantly modify the disease course, although they do reduce disease symptoms It is important therefore to develop new treatments that can slow or prevent the progression of AD. In order to do this, we need to understand the events that occur in AD brain that cause nerve cells to die. This project will examine the relationship between three important proteins, amyloid, Fyn, and tau, that may come together to play a critical role in nerve cell death in AD. We have already found that binding of tau to Fyn can cause these proteins to move to parts of cells where they are more likely to be detrimental and result in them dying. We also know that amyloid is toxic to nerve cells. Here, we plan to investigate the influence of amyloid on tau and Fyn interactions, as well as on their positions inside nerve cells. We will also identify other proteins involved in the process that leads to dying nerve cells so that we can understand the mechanism involved. Our results may help develop new treatments for AD that interfere with tau and Fyn binding and reduce nerve cell death and dementia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigating attentional function and cognitive fluctuations in Lewy body dementia
Funder: Alzheimer's Research UK

Abstract: Lewy body dementia (LBD) is the second most common cause of degenerative dementia after Alzheimer’s disease in older people and includes dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD). LBD is a progressive condition that ultimately leads to death. People with LBD suffer considerable disability and distress and can experience problems with movement control, visual hallucinations and fluctuations in their ability to think clearly. In particular, the fluctuations seem to be particularly common in LBD but we do not understand yet what causes them. The proposed PhD study seeks to understand more about the causes of the fluctuations in thinking ability that occur in LBD. The student will look at how activity patterns change in the brains of people with LBD using electrical scalp recordings when they are doing a simple picture task on a computer. These tests will tell us more about the cause of the fluctuations, which brain areas are involved in fluctuations and how the activity of brain cells (neurones) is altered in LBD. Knowing more will help us diagnose the condition better and earlier. It will also help us in developing effective treatments to improve the quality of life for people with LBD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Involvement of a brain “Metaflammasome” in neurodegeneration
Funder: Alzheimer's Research UK

Abstract: Risk factors for Alzheimer’s disease (AD), including ageing, obesity, diabetes, high blood pressure and brain protein accumulation are known to provoke long-term inflammation. Many of the genes identified in recent studies as contributing to risk for AD are also involved in lipid metabolism and inflammation. Long-term inflammation in any organ induces cell damage and dysfunction. Recent evidence implicates a group of molecules (known as the “metaflammasome”) in mediating the effect of these different risk factors in causing long-term inflammation. PKR, the main component of this group, is known to occur in AD in association with brain inflammation. Consequently, we hypothesize that known risk factors for AD activate these molecules causing brain inflammation, cell death and dementia.Using samples from patients with AD and a mouse model involving increasing lipids or directly provoking inflammation, we will examine the expression of these molecules in association with brain inflammation and cell death. In addition, by using either a drug to block one of the molecules, or a mouse which has been genetically modified to lack this molecule, we will observe the consequences on brain cells and inflammation. In the future reducing activation of these molecules could prevent brain damage in AD.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: O-GlcNAc as a strategy for the treatment of tauopathies
Funder: Alzheimer's Research UK

Abstract: The class of neurodegenerative diseases collectively termed the tauopathies result from the aggregation of a toxic form of tau in with it is hyper(over) phosphorylated. Less well known is that tau phosphorylation is reciprocal to its modification with a sugar termed “O-GlcNAc” and that O-GlcNAc levels are, concomitantly, reduced in the diseased brain. Proof of concept studies show that the toxic form of tau can be significantly reduced using a small molecule strategy that therapeutically raises tau-O-GlcNAc levels. We aim to study, in detail, the human enzymes responsible for this effect, providing a platform on which to design the next generation of inhibitors providing a new approach to the treatment of tauopathies such as frontotemporal dementia.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Alzheimer’s disease and posterior cortical atrophy: cognitive and neuroimaging studies of visual dysfunction
Funder: Alzheimer's Research UK

Abstract: The majority of individuals with Alzherimer's disease (AD) experience memory problems as their first and most prominent symptom. However, there are less common variants in which the disease causes a different pattern of problems by affecting different parts of the brain. For example, posterior cortical atrophy (PCA) is a progressive syndrome characterised by dramatic loss of visual function (i.e. the ability to see what and where things are). PCA is caused not by problems with the eyes but by AD (or occasionally other degenerative diseases) affecting regions at the back of the brain which are involved in interpreting information about the visual world around us. This project investigates variation in AD, and particularly the disease mechanisms underpinning PCA. In this study, 50 PCA patients, 50 AD patients and 50 healthy control participants will be compared and contrasted at multiple time-points using a combination of clinical, neuropsychological, neuroimaging, genetic and pathological techniques. These comparisons will identify factors which cause the site of earliest change, the rate of progression and the pattern of progression to vary so greatly within this single disease population. These factors have relevance for the diagnosis, prognosis and response to therapy of both typical and atypical AD.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigation into novel neuronal functions of plasma membrane-associated and secreted tau
Funder: Alzheimer's Research UK

Abstract: Alzheimer’s disease (AD) is characterized by loss of memory due to progressive death of the nerve cells in the brain. In early stages of AD, connections between nerve cells become impaired so they cannot properly communicate, which may lead to cell death. Therefore, an effective treatment of AD would prevent death of nerve cells by targeting these early changes in the brain. New data suggest problems in cell communication are caused by abnormalities in a protein called tau. To understand how brain connections become dysfunctional in AD, we will examine a new role for tau in nerve cell communication. We will use a cutting-edge technique to directly observe, for the first time, connections between nerve cells which contain abnormal tau. We will use chemicals to specifically activate or inhibit nerve cells, so we can understand how tau is involved in communication, both inside the cell and between cells. Finally, we will perform experiments which will identify new proteins which interact with tau. Using this combination of approaches we will characterize a new function for tau in nerve cell communication, with the goal of identifying new targets for drugs that may halt or prevent progression of AD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Resting-state functional connectivity networks in different variants of Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: Whilst most patients with Alzheimer’s disease (AD) show a progressive decline in their memory as their first and most prominent symptom, there are a number of AD patients who present with very different problems Some patients have difficulties seeing and recognizing objects and are often diagnosed with Posterior Cortical Atrophy (PCA), whilst others have mainly language difficulties often referred to as logopenic progressive aphasia (LPA). The mechanisms that drive AD pathology to cause these different cognitive problems are currently unknown. Disruptions of specific functional networks mediating memory, language and vision, are suggested to contribute to the different problems these patients experience. The project uses functional imaging to assess connectivity in specific networks in 50 amnestic, 35 PCA, and 20 LPA patients. The relationship between disrupted connectivity and underlying pathological and metabolic changes, cell loss and cognitive decline will be examined. The findings will provide valuable insights into why people experience different symptoms despite having the same underlying AD pathology. This fellowship will further establish an important link between the UK and the US that will be beneficial for studying rare variants of AD using multiple imaging modalities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Systemic and central inflammation in Dementia with Lewy Bodies
Funder: Alzheimer's Research UK

Abstract: Dementia with Lewy Bodies accounts for up to one quarter of all cases of dementia in the elderly. It has many similarities to Alzheimer’s Disease but patients with the disease often have disturbing hallucinations and a variable memory state. These symptoms make it very hard to diagnose and to tell apart from the confusion that some elderly people get when they have an infection. Dementia with Lewy Bodies has not been well researched but we think that the reason it may look like delirum is that the condition is actually caused (or at least made a lot worse) by an overactive immune system in the blood and the brain that makes it look like an infection is taking place. We want to see if this is the case and if we can prove it we will be in a much better position to develop new treatments, based on existing drugs that can dampen down the immune response. We also think that our research will allow us to develop a blood test for the disease that means that Doctors can diagnose the condition early without the need for costly brain scanning.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The use of laser capture microdissection to aid in the understanding of disease mechanisms
Funder: Alzheimer's Research UK

Abstract: Frontotemporal lobar degenerations (FTLDs) are a group of conditions with loss of nerve cells in the frontal and temporal lobes of the brain. Through a project grant funded by ARUK, clinical and pathological correlations have emerged from studying this large FTLD cohort at Queen Square Brain Bank / Dementia Research Centre. The neuropathological hallmarks found in FTLDs are manifested from proteins becoming defective and forming cellular inclusions. The normal functions of these proteins are involved in the movement of ribonucleic acids from the cell nucleus to the cytoplasm. We have shown for the first time that additional proteins involved in the movement of RNA are also found in the neuropathological hallmarks of FTLDs, suggesting these may play a role in the disease progression. Utilising our unique collection of FTLD cases we aim to identify differences between pathologically affected and unaffected brain areas. Identifying pathological events occurring early in the development of FTLDs could potentially be targeted for early therapeutic interventions to slow disease progression. The purchase of a Leica laser capture microscope would allow use to dissect out individual cells from post-mortem tissue and analyse the genetic material and protein from these cell populations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Multi-transmit capability for 3T MRI scanner for high spatial resolution imaging of brain
Funder: Alzheimer's Research UK

Abstract: Objective diagnostic techniques are urgently needed to identify Alzheimer’s disease (AD) early so that the available treatment would benefit patients as efficiently as possible. We are working towards improved magnetic resonance imaging (MRI) protocols for early detection of AD before significant memory loss has taken place. Our work focuses on the hippocampus, a small brain structure deep in the temporal lobe, because hippocampus is affected in AD resulting in memory loss. MRI studies have demonstrated that hippocampus shrinks at accelerated rate in Alzheimer’s patients. Owing to the technical development of MR scanners and techniques, it is now possible to look in more detail at hippocampal structure to identify patients with very early AD before significant clinical symptoms Early diagnosis not only benefits established and investigational treatments, but it may also slow or halt disease progression. The current MRI work on AD in Bristol, a clinical drug trial as well as several planned dementia MR imaging projects in Bristol would greatly benefit from MR scanner upgrade, the so-called multi-transmit capability. The multi-transmit capability will improve the resolution of MR images and thereby, makes it possible to examine hippocampus and other brain structures in great detail for early detection of AD.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: NEUROLOGICAL
Title: C9orf72: Yeast-2-hybrid verification for biological investigation of protein function
Funder: Alzheimer's Research UK

Abstract: Recently, it has been shown that a mutation in the gene C9orf72 is the most common genetic cause of frontotemporal dementia (FTD) identified to date. Interestingly, the same mutation can also cause motor neuron disease (MND) with equal frequencies. This mutation is found in 1 out of every 12 patients with FTD or MND. However, C9orf72 is a completely uncharacterised gene and nothing is known about it's function. Therefore, to try and understand what the function of C9orf72 is we have used a technique to identify which other proteins interact with C9orf72. We have identified 12 potential binding partners for C9orf72, however, this technique can also bring up false positive results. We are requesting funds to verify which of these 12 are real binding partners of C9orf72 to help us understand it's biological function and it's role in causing FTD or MND.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Alzheimer’s-specific changes in an Ageing Drosophila Alzheimer's model
Funder: Alzheimer's Research UK

Abstract: The risk of developing sporadic Alzheimer’s Disease (AD) increases dramatically with age, with the risk doubling every five years after the age of 65. This is becoming increasingly important as individuals are living longer. AD is associated with the presence of deposits of amyloid (comprising Abeta peptide) in the brain. Despite the fact that ageing is the biggest risk factor for AD, little is understood about how ageing affects these peptides and leads to manifestation of disease symptoms We use a model of AD in the fruitfly Drosophila which replicates many features of the disease including neuronal dysfunction and premature death. We have used this model to investigate age-specific changes that happen specifically in AD flies. We have selected a number of genes which are expressed differently in AD flies compared to normal flies and we are looking at the effect of manipulating their levels in AD and control flies to investigate the importance of observed changes. We are also investigating whether these changes are observed in a human AD neuronal model. By doing this we aim to make progress in understanding the mechanisms that increase the risk of AD as we age and towards new biomarkers and treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: PGC1-alpha as therapeutic target for Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: The PPARγ coactivator-1α (PGC-1α) is a transcriptional regulator which has a potential role in the regulation of type 2 diabetes and whose levels are increased during exercise. We have found that the levels of PGC-1α are reduced in the brain of Alzheimer’s disease (AD) patients. Furthermore, PGC-1α could be protective against AD because we have shown that PGC-1α reduces the generation of amyloid-β (Aβ) in cell culture by regulating the levels of BACE1, the main enzyme involved in Aβ production. We are currently carrying out experiments to determine whether PGC-1α decreases AD pathology in the brain by delivering PGC-1α in to the brain of AD animal model mediated by lentiviral vectors. This will allow us testing if PGC-1α can be candidate for gene therapy in the treatment of AD. In these animals we are investigating if PGC-1α decreases the brain pathology associated with AD (Aβ plaques and neurofibrillary tangles) and improves memory as well. Because we haven't been able to finalize these experiments in our current grant,we would request an emergency funding in order to be able to complete this part of the project.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Calcium abnormalities associated with neurodegeneration in Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: This project will investigate events that we believe may be key steps in triggering disrupted nerve cell function in Alzheimer's disease (AD). We will focus on events that increase the activity of calpain, an enzyme that breaks down other proteins. Calpain is stimulated when calcium enters nerve cells. Normally there is a balance between the amount of calcium entering and leaving nerve cells and part of this process is controlled by a protein that acts as a chemical pump - exchanging calcium inside the cells with external sodium. In AD, excess calcium enters nerve cells and stimulates calpain, which breaks down the pump and prevents the excess calcium from leaving the nerve cells. The result is an abnormally high level of calcium inside cells that disrupts normal nerve function. We believe that the breakdown of the sodium/calcium exchange pump by calpain is important in AD and this project aims to investigate this process in more detail. This work might reveal novel therapeutic targets for the treatment of AD and related disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL