NIHRDataInsights/HRCSData huggingface dataset:
Title: Downsized Cell-derived Peptides as Potent Inhibitors of aS Toxicity
Funder: Alzheimer's Research UK

Abstract: Aggregation of the alpha-Synuclein (aS) protein inside dopamine producing cells leads to PD by forming toxic Lewy bodies that interfere with normal brain function. We will search vast peptide-libraries inside living cells to identify those that effectively block aS toxicity. Specifically, Protein-fragment Complementation Assays (PCAs) will be used by fusing aS to one half of an essential enzyme, with the peptide library fused to the second half. Only peptides that bind aS will recombine the two halves of the enzyme, thereby activating it leading to cell survival. However, aS is toxic leading to slow cell growth, meaning successful peptides are only selected if they bind aS and, most importantly, reduce associated toxicity by locking it into a non-toxic state. Novelty lies in the fact that peptide selection is undertaken entirely inside living cells, with no assumptions made regarding mechanism of binding. Intracellular selection removes promiscuous peptides that bind to other proteins, as well as those that are unstable, insoluble, and degraded by enzymes. Promising compounds will be characterised using a range of biophysical, structural, and cell-based experiments to i) increase understanding of how clumping and toxicity are coupled ii) generate molecules for future use in PD diagnostics and prevention.

Lay abstract: Aggregation of the alpha-Synuclein (aS) protein inside dopamine producing cells leads to PD by forming toxic Lewy bodies that interfere with normal brain function. We will search vast peptide-libraries inside living cells to identify those that effectively block aS toxicity. Specifically, Protein-fragment Complementation Assays (PCAs) will be used by fusing aS to one half of an essential enzyme, with the peptide library fused to the second half. Only peptides that bind aS will recombine the two halves of the enzyme, thereby activating it leading to cell survival. However, aS is toxic leading to slow cell growth, meaning successful peptides are only selected if they bind aS and, most importantly, reduce associated toxicity by locking it into a non-toxic state. Novelty lies in the fact that peptide selection is undertaken entirely inside living cells, with no assumptions made regarding mechanism of binding. Intracellular selection removes promiscuous peptides that bind to other proteins, as well as those that are unstable, insoluble, and degraded by enzymes. Promising compounds will be characterised using a range of biophysical, structural, and cell-based experiments to i) increase understanding of how clumping and toxicity are coupled ii) generate molecules for future use in PD diagnostics and prevention.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cholinergic ResponsE in Early lewy body Disease (CREED) study
Funder: Alzheimer's Research UK

Abstract: Lewy body dementia (LBD) includes both people with Parkinson’s disease dementia and dementia with Lewy bodies. Research has shown that there is a loss of brain chemicals such as acetylcholine in LBD. This contributes to problems with thinking, hallucinations and walking. Cholinesterase inhibitors (e.g. Donepezil) are drugs used to help increase levels of acetylcholine. However, whilst these drugs can help some people with LBD, not everyone responds. It also is not currently clear whether they help at early disease stages i.e. before dementia is present. We are currently doing a trial with Donepezil in people with early LBD and are looking to develop new measures (‘biomarkers’) of the function of brain systems that use acetylcholine. Our biomarkers include brain scans (magnetic resonance imaging), and recordings from brain electrical activity and body worn activity sensors. Critically, we want to test whether these biomarkers are truly tuning into acetylcholine function in LBD. To do this, we will compare these measures against a specialist brain scan that gives a direct measure of functioning of brain cells that produce acetylcholine. These biomarkers will help us work out who might best respond to treatment and develop drugs that better target brain systems that use acetylcholine.

Lay abstract: Lewy body dementia (LBD) includes both people with Parkinson’s disease dementia and dementia with Lewy bodies. Research has shown that there is a loss of brain chemicals such as acetylcholine in LBD. This contributes to problems with thinking, hallucinations and walking. Cholinesterase inhibitors (e.g. Donepezil) are drugs used to help increase levels of acetylcholine. However, whilst these drugs can help some people with LBD, not everyone responds. It also is not currently clear whether they help at early disease stages i.e. before dementia is present. We are currently doing a trial with Donepezil in people with early LBD and are looking to develop new measures (‘biomarkers’) of the function of brain systems that use acetylcholine. Our biomarkers include brain scans (magnetic resonance imaging), and recordings from brain electrical activity and body worn activity sensors. Critically, we want to test whether these biomarkers are truly tuning into acetylcholine function in LBD. To do this, we will compare these measures against a specialist brain scan that gives a direct measure of functioning of brain cells that produce acetylcholine. These biomarkers will help us work out who might best respond to treatment and develop drugs that better target brain systems that use acetylcholine.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Neuronal hBACE1: The link between Alzheimer’s disease and diabetes?
Funder: Alzheimer's Research UK

Abstract: The vast majority of dementia cases (>90%), including Alzheimer’s disease (AD), are sporadic i.e. not attributable to a single genetic change. This implies that lifestyle and other non-inherited factors must play a major causative role. A number of studies have confirmed that diabetes and obesity are such factors, however, their connection with AD is still not clear. We have recently developed a mouse model (called PLB4) that we consider to model sporadic forms of AD. It is not based on rare familial AD but instead carries the human gene responsible for the generation of toxic amyloid proteins in the brain. Surprisingly, PLB4 mice developed not only AD-like but also diabetic symptoms. This suggests a close link between the two diseases. We would now like to conduct a thorough investigation of this mouse, alongside additional experimental groups that will validate the underlying mechanisms and study the relevant brain regions involved in AD and diabetes. To assess whether AD pathology triggers diabetes, and/or vice versa, we would also compare compounds that normalise diabetes with treatments that normalise AD pathology. This work is essential to establish connections between AD and life-style related risk factors, and instruct the development of better treatment strategies.

Lay abstract: The vast majority of dementia cases (>90%), including Alzheimer’s disease (AD), are sporadic i.e. not attributable to a single genetic change. This implies that lifestyle and other non-inherited factors must play a major causative role. A number of studies have confirmed that diabetes and obesity are such factors, however, their connection with AD is still not clear. We have recently developed a mouse model (called PLB4) that we consider to model sporadic forms of AD. It is not based on rare familial AD but instead carries the human gene responsible for the generation of toxic amyloid proteins in the brain. Surprisingly, PLB4 mice developed not only AD-like but also diabetic symptoms. This suggests a close link between the two diseases. We would now like to conduct a thorough investigation of this mouse, alongside additional experimental groups that will validate the underlying mechanisms and study the relevant brain regions involved in AD and diabetes. To assess whether AD pathology triggers diabetes, and/or vice versa, we would also compare compounds that normalise diabetes with treatments that normalise AD pathology. This work is essential to establish connections between AD and life-style related risk factors, and instruct the development of better treatment strategies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Role of glucose metabolism in C9orf72 repeat expansion toxicity
Funder: Alzheimer's Research UK

Abstract: Our brains consume 20% of our body’s energy, however, nerve cells can’t store energy or use fat as a fuel so they have to generate all their energy from sugar. The brain has complex molecular mechanisms to ensure a constant supply of sugar to nerve cells, but in people with dementia this system gradually breaks down as disease progresses. We recently discovered that improving sugar delivery helps nerve cells cope with the effects of toxic proteins associated with Alzheimer’s disease. We plan to extend this work to another type of dementia: Fronto Temporal Dementia(FTD), the second most common early onset dementia, to understand if glucose metabolism effects dementias generally. We will genetically increase sugar delivery to nerve cells of a fly model of FTD to see if we can improve its symptoms. Fruit-flies make excellent models to study dementia as they have a well defined brain and don’t live very long, allowing us to study disease progression throughout their whole lifespan (important in diseases affecting older people). We will confirm the discoveries in mouse models and in cells donated by FTD patients. The biological mechanisms identified in this research could be potential targets for new dementia drugs.

Lay abstract: Our brains consume 20% of our body’s energy, however, nerve cells can’t store energy or use fat as a fuel so they have to generate all their energy from sugar. The brain has complex molecular mechanisms to ensure a constant supply of sugar to nerve cells, but in people with dementia this system gradually breaks down as disease progresses. We recently discovered that improving sugar delivery helps nerve cells cope with the effects of toxic proteins associated with Alzheimer’s disease. We plan to extend this work to another type of dementia: Fronto Temporal Dementia(FTD), the second most common early onset dementia, to understand if glucose metabolism effects dementias generally. We will genetically increase sugar delivery to nerve cells of a fly model of FTD to see if we can improve its symptoms. Fruit-flies make excellent models to study dementia as they have a well defined brain and don’t live very long, allowing us to study disease progression throughout their whole lifespan (important in diseases affecting older people). We will confirm the discoveries in mouse models and in cells donated by FTD patients. The biological mechanisms identified in this research could be potential targets for new dementia drugs.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Deciphering the causal relationship between blood metabolic biomarkers and Alzheimer’s Disease
Funder: Alzheimer's Research UK

Abstract: Better understanding of the biological mechanisms underlying Alzheimer’s disease (AD) is required. Studies have demonstrated the promise of using small molecules in blood, known as metabolites, as good biomarkers for AD. The aim of this study is to look for changes in blood metabolites associated with early AD diagnosis and progression and to ascertain whether these metabolic biomarkers are causal to AD, instead of being for example a result of AD. Specifically this project will a) analyze the blood metabolite profiles of AD patients, individuals with mild cognitive impairment (MCI) and healthy controls; b) investigate whether changes in metabolite levels associated with AD are causal to AD; c) incorporate biological information, such as protein and gene abundance levels, to understand more about the biological context in which the identified metabolites operate; d) compare findings from the analyses on blood samples with those in available cerebrospinal fluid (CSF) and with the composition of the intestinal microbiome from overlapping samples. This project will use large well-characterized cohorts and sophisticated statistical approaches. This is a novel and timely study, the outcomes of which will be the identification of modifiable targets associated with AD and the development of effective interventions.

Lay abstract: Better understanding of the biological mechanisms underlying Alzheimer’s disease (AD) is required. Studies have demonstrated the promise of using small molecules in blood, known as metabolites, as good biomarkers for AD. The aim of this study is to look for changes in blood metabolites associated with early AD diagnosis and progression and to ascertain whether these metabolic biomarkers are causal to AD, instead of being for example a result of AD. Specifically this project will a) analyze the blood metabolite profiles of AD patients, individuals with mild cognitive impairment (MCI) and healthy controls; b) investigate whether changes in metabolite levels associated with AD are causal to AD; c) incorporate biological information, such as protein and gene abundance levels, to understand more about the biological context in which the identified metabolites operate; d) compare findings from the analyses on blood samples with those in available cerebrospinal fluid (CSF) and with the composition of the intestinal microbiome from overlapping samples. This project will use large well-characterized cohorts and sophisticated statistical approaches. This is a novel and timely study, the outcomes of which will be the identification of modifiable targets associated with AD and the development of effective interventions.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Noradrenergic treatment for the symptoms of Alzheimer's disease.
Funder: Alzheimer's Research UK

Abstract: Brain changes in Alzheimer’s Dementia (AD) follow a predictable anatomical distribution and sequence and appear first in a small structure at the base of the brain, called the locus coeruleus (LC). The LC contains most of the brain’s cells that produce a neurotransmitter called noradrenaline, which has important roles in thinking, memory and control of behaviour. Researchers and clinicians have long suspected that changes to the LC play an important role in early problems in remembering things and concentrating in AD. However, the LC has been difficult to study because it is a very small structure and we still know very little about the role of the LC in early AD. My previous work established the feasibility of measuring the LC in healthy older people. I discovered that age-related decline in LC structure and function is associated with a decline in episodic memory. With this fellowship, I will apply this technique to AD and also test whether a pharmacological agent which boosts noradrenaline function can improve memory and the ability to concentrate in early AD. If successful, this research will open new avenues on how to detect AD earlier and improve symptoms in early AD.

Lay abstract: Brain changes in Alzheimer’s Dementia (AD) follow a predictable anatomical distribution and sequence and appear first in a small structure at the base of the brain, called the locus coeruleus (LC). The LC contains most of the brain’s cells that produce a neurotransmitter called noradrenaline, which has important roles in thinking, memory and control of behaviour. Researchers and clinicians have long suspected that changes to the LC play an important role in early problems in remembering things and concentrating in AD. However, the LC has been difficult to study because it is a very small structure and we still know very little about the role of the LC in early AD. My previous work established the feasibility of measuring the LC in healthy older people. I discovered that age-related decline in LC structure and function is associated with a decline in episodic memory. With this fellowship, I will apply this technique to AD and also test whether a pharmacological agent which boosts noradrenaline function can improve memory and the ability to concentrate in early AD. If successful, this research will open new avenues on how to detect AD earlier and improve symptoms in early AD.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Regulatory genomic variation in rodent models of amyloid and tau neuropathology
Funder: Alzheimer's Research UK

Abstract: The changes in the brain associated with Alzheimer’s disease have been well described but the specific mechanisms involved in the onset and progression of the disease are still unknown. We will examine several strains of mice that model aspects of human Alzheimer’s disease including both amyloid and tau pathology. The advantage of using mice is that they can be investigated at multiple stages through the development of pathology, enabling us to assess critical disease-related processes. We will test the hypothesis that the development of pathology is associated with changes in the activity of genes in affected brain regions. We will relate changes in gene function to measures of brain pathology, and will subsequently test specific changes in our extensive human Alzheimer’s disease datasets. The final stage of this project will involve targeted studies of new treatments undertaken (and funded) by our collaborators at Eli Lilly, representing a considerable in-kind contribution that will maximize the translational outcomes of this study. The project brings together world-class experts in genomics, informatics and neuroscience, and represents a novel approach for identifying the mechanisms involved in the progression of Alzheimer’s disease.

Lay abstract: The changes in the brain associated with Alzheimer’s disease have been well described but the specific mechanisms involved in the onset and progression of the disease are still unknown. We will examine several strains of mice that model aspects of human Alzheimer’s disease including both amyloid and tau pathology. The advantage of using mice is that they can be investigated at multiple stages through the development of pathology, enabling us to assess critical disease-related processes. We will test the hypothesis that the development of pathology is associated with changes in the activity of genes in affected brain regions. We will relate changes in gene function to measures of brain pathology, and will subsequently test specific changes in our extensive human Alzheimer’s disease datasets. The final stage of this project will involve targeted studies of new treatments undertaken (and funded) by our collaborators at Eli Lilly, representing a considerable in-kind contribution that will maximize the translational outcomes of this study. The project brings together world-class experts in genomics, informatics and neuroscience, and represents a novel approach for identifying the mechanisms involved in the progression of Alzheimer’s disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying and verifying non-coding genetic causes of amyotrophic lateral sclerosis
Funder: Wellcome Trust

Abstract: Amyotrophic lateral sclerosis (ALS or motor neuron disease) is aggressive and relatively common. 10% is familial, but even in sporadic ALS estimated heritability is 61%. The complex inheritance patterns underlying the majority of disease are poorly understood. I aim to discover the basis of this missing heritability to inform translational research. Genome-wide association studies suggest the majority of missing ALS heritability is distributed throughout non-coding DNA. Within these regions, established methods for identifying disease-associated coding variants are either ineffective or underpowered. I have developed pioneering methodology to detect ALS-associated genetic variation within gene-enhancers and promoters - non-coding DNA elements that control gene expression. Using whole genome sequencing (WGS) data I identified genome-wide significant ALS-associated variation in enhancers controlling expression of METTL8 (p=1.7E-06). Moreover, I used a non-linear model to identify new ALS-association within gene-promoters which was twice as effective as standard methodology. I will validate my discoveries using a high-throughput reporter; top candidates will be modelled in vitro and in vivo. I will develop my methodology to be cell-specific by profiling of epigenomic features within normal motor neurons. I intend to construct a complete genetic architecture for sporadic ALS to enable individualised diagnostic and prognostic prediction through WGS.

Lay abstract: Amyotrophic lateral sclerosis (ALS or motor neuron disease) is untreatable and common. 10% of patients have a family history but even without that, 61% of the risk of ALS is genetically determined, but poorly understood. I aim to discover the basis of this missing genetic causation. 99% of DNA does not encode proteins; ‘non-coding’ regions regulate expression of protein-coding regions. Missing genetic causes of ALS are predominantly non-coding, out of reach of current methods. I have developed pioneering methodology to pinpoint ALS-associated genetic variation within non-coding DNA. I have detected significant novel ALS-association within non-coding DNA, including regions controlling expression of the METTL8 gene; this could lead to new ALS treatments. I plan to improve my methodology by integrating motor neuron-specific DNA structure. I will validate my discoveries using cell models. Finally I will develop a genetic test to provide diagnostic and prognostic information to ALS patients in the clinic.

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