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The University of Southampton
BRAIN UK

Lay Summaries of studies supported by BRAIN UK by category: Alzheimer's disease.

BRAIN UK Ref: 11/007
How do ageing processes contribute to Alzheimer’s disease?
Dr D Boche, University of Southampton

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is associated with the accumulation of a particular molecule (called tau protein) in the central nervous system. The incidence of AD increases exponentially with age which implies that mechanisms associated with ageing may also be involved with the initiation and progression of AD. In an animal model based upon the fruit fly, manipulations to three particular biological pathways have been shown to extend life and these particular pathways have also been implicated in AD. The researcher has established a model of HD in the fruit fly in which abnormal accumulations of tau protein result in disrupted cellular transport, disruption to nerve cell signaling, reduced life-span and behavioural changes.

This study will apply specific staining techniques to tissue from AD-affected brains with age-matched controls and gender-matched controls from a younger cohort in order to demonstrate molecules associated with ageing to determine if any correlation exists between disease duration and the expression of molecules already established to be associated with AD.

Project Status: Closed

BRAIN UK Ref: 12/009
Investigation into the impact of systemic inflammation due to infection on microglial phenotype and its contribution to Alzheimer's disease neuropathology
Dr D Boche, University of Southampton

When we have an infection we feel sick and uninterested in things. This is known as “sickness behaviour” and is temporary. 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.

Project Status: Closed

Research Outputs: Publication; Grant Application; Abstract; Presentation x 10; Poster x 7

DatePublication title
2018 Systemic Infection Modifies the Neuroinflammatory Response in Late Stage Alzheimer's Disease

BRAIN UK Ref: 13/001
Are neurodegenerative diseases and gliomas inverse comorbidities?
Dr F Roncaroli, Imperial College, London

The study of the association of different diseases and how they influence each other has proved a promising venue to elucidate the mechanisms underlying several common conditions such as diabetes, cancer and brain degeneration. “Comorbidity” is used when one disease occurs at higher frequency than normal in patients that already have a common condition and “inverse comorbidity” when one disease occurs at a lower than expected frequency in people with a common condition. Patients with degenerative conditions of the brain such as Alzheimer’s disease and Parkinson’s disease often have lower occurrence of cancer than the any other individual of similar age. This evidence led to suggesting that patients with brain degeneration are somehow protected to developing cancer.
The most common and most aggressive brain tumour is called glioblastoma. It occurs at any age but it is vastly more frequent between 50-70 years. Glioblastoma is a killer. Patients with this form of cancer rarely survive longer than 12-14 months form the time the tumour is diagnosed. Cancer cells that constitute glioblastoma can interact with the cells of the normal brain and exploit them to better survive, grow and invade the surroundings.
At the UK Parkinson’s Disease tissue bank at Imperial College, London, we have observed that patients with Parkinson’s disease are unlikely to develop glioblastoma. Such observation was supported by the analysis of death certificates in the UK documenting a much lower than expected occurrence of glioblastoma in patients who died of Parkinson’s and Alzheimer’s disease.
This study aims to understand if the brain affected by degenerative conditions has anything that stops glioblastoma to develop. We have therefore enquired Brain UK to run a survey of the over 36,000 records available for the association between Parkinson’s and Alzheimer’s disease and glioblastoma.

Project Status: Closed

Research Outputs: Abstract

BRAIN UK Ref: 13/010
Pilot study of cholesterol, lipids and LDL in Alzheimer’s disease
Prof. J A R Nicoll, University of Southampton 

There are certain inherited genetic factors that influence the risk of a person getting Alzheimer’s disease. This tells us that the proteins produced by these genes must be important in this type of brain malfunction. The most important of these proteins, known as apoE, controls transport of cholesterol and other lipids (fats) contained within particles (“lipoprotein particles”) between cells. One of the problems of studying cholesterol and fats in the brain is that commonly used methods results in them being dissolved out of the tissue while it is prepared for study under the microscope. In this pilot study we examined tissue sections from frozen samples of brain tissue which retains the cholesterol and fats and tested different staining methods to demonstrate them under the microscope. We explored whether accumulation of cholesterol and fats occurs in the brain and how this relates to the known microscopic abnormalities in Alzheimer’s disease. We found that some evidence for accumulation of fats around blood vessels and within nerve cells in the brains of people with Alzheimer’s disease. We also found that LRP1, a protein to which the lipoprotein particles attach, is present in some of the brain abnormalities in Alzheimer’s disease. This pilot study has developed methods to study cholesterol, lipids and associated proteins in the brain in Alzheimer’s disease which will be used in further investigations.

Project Status: Active

Research Outputs: Grant Application; Presentation x 4

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BRAIN UK Ref: 14/002
Age-modified forms of amyloid-β in a Drosophila model of neurodegeneration and in the brain of Aβ immunised Alzheimer's disease patients
Dr D Boche, University of Southampton 

Alzheimer Disease (AD) is the commonest form of dementia, with ageing as the main risk factor. There are currently over 6 million people with dementia in the European Union (EU). The increasingly ageing population makes AD an economic and social burden for our society, thus investigating the pathological mechanisms of AD and the characterization of the pharmacological targets are research priorities. Deposition of amyloid-Beta (Aβ) is considered a driving force in AD pathogenesis, and the major target for vaccination.
During ageing in humans, the molecules of AD pathogenesis undergo ageing processes resulting in biological modifications that influence protein formation and function. Specially, pyroglutamate-modified Aβ (pEAβ) seems to be a key participant in AD pathology. Accordingly, the identification of markers of protein ageing is important to comprehend AD pathogenesis with relevance in therapies. Indeed, Aβ immunotherapy did not prevent dementia in the treated patients, potentially due to the absence of elimination of aged-modified Aβ implicated in the disease. We propose to take advantage of the unique cohort of human unimmunized and immunized AD brains at UoS to study if pEAβ formation and its interaction with tau, the other deposited molecule in AD, has been modified by Aβ vaccination. The results will expand the Aβ characterization as a pharmacological target, and support the rational design of a second generation of “Aβ vaccination”.

Project Status: Closed

Research Outputs: Publication; Abstract; Presentation x 3; Posters x 9

DatePublication title
2018 Pyroglutamate and Isoaspartate Modified Amyloid-Beta in Ageing and Alzheimer's Disease

BRAIN UK Ref: 14/003
Studying the role of TUBA8 (tubulin alpha 8) in brain disorders
Dr M R Abdollahi, University of Southampton 

Alzheimer’s disease (AD) is the most common type of dementia. The nerve cells are abnormal in this disease. Clumps of protein called tangles containing tau form inside the nerve cells and correlate with the severity of dementia. tau has a role in microtubule stability and microtubules are fundamental to cell skeleton and intracellular trafficking. However, surprisingly, little work has been done in the human brain to understand how the microtubules and tubulins are affected in Alzheimer’s disease. We have recently identified a mutation in a gene in association with a neurological disorder. This gene is involved in important cellular functions. In this project, we investigated the gene using immunostaining in five AD patients and five age matched controls from BRAIN UK. The results show an interesting difference between the cases and the controls. This is a very important observation and we are going to reproduce, validate and quantify this in a greater sample size.

Project Status: Active

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BRAIN UK Ref: 14/013
Functional characteristics of rare risk variants in TREM2 associated with Alzheimer's disease
Dr A Hodges, King's College London 

Perhaps the most exciting, recent finding in the genetics of Alzheimer’s disease (AD), has been the identification of rare changes in the TREM2 gene which increase vulnerability to AD. Evidence suggests TREM2 is part of a small cluster of functionally related genes which are active in microglia. Microglia are an important cell in the brain responsible for maintaining a healthy brain and generating an immune response. A loss in normal TREM2 function is predicted to lead to a failure in the clearance of damaged brain material and inappropriate immune activation which can damage healthy tissue. We have screened ~4,000 people who have been participating in our genetic and biomarker studies at the IoPPN. Through collaboration with other UK brain banks we have identified an extremely important group of around 19 individuals with AD-associated TREM2 changes for whom post mortem brain tissue is available. Studying brain tissue from these people and comparing it to other people with AD will firstly, provide us with clues to further understand the contribution of this gene to AD and secondly, will generate data which will enable us to validate a cell model of TREM2 dysfunction we are generating in a separate study for the purposes of compound screening and drug development for AD. Our project will characterise morphological and activation changes in microglia and compare changes in gene and protein expression in these cells.

Project Status: Active

Research Outputs: Presentation x 3; Poster x 3

 

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BRAIN UK Ref: 15/013
Exploratory study: use of MultiOmyx to investigate the pathology of Alzheimer’s disease
Prof. J Nicoll, Southampton University 

Alzheimer’s disease is the commonest cause of dementia (failure of mental function with age). In the brain in Alzheimer’s disease there are many different abnormalities, affecting many different proteins. Understanding of how the different proteins interact is limited because of technical constraints. For example, the proteins involved include Aβ, tau, apoE, which are located in different structures in the brain; inside and outside cells (including nerve cells and supporting cells) and within the walls of blood vessels. The limitation in our understanding comes about because in any one sample of brain tissue it is only possible to identify up to about 3 proteins at a time. Collaborators at GE Global Research are developing new technology called MultiOmyx which allows examination of up to 60 different proteins in the same tissue sample. This is a tremendous technical advance and has the potential to increase our understanding of the brain abnormalities in Alzheimer’s disease and other diseases affecting the brain. In this study we wish to work in collaboration to explore the use of MultiOmyx in Alzheimer’s disease, in this pilot study by using brain tissue from 6 patients with Alzheimer’s disease and 6 elderly normal subjects for comparison. 

Project Status: Active

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BRAIN UK Ref: 16/013
DNA/RNA instability in spinal muscular atrophy
Dr Sim K. Singhrao, University of Central Lancashire 

During the development of Alzheimer’s disease, proteins build up in the brain to form structures called 'plaques' and 'tangles'. This leads to the loss of connections between nerve cells, and eventually to the death of nerve cells and loss of brain tissue. This means that gradually, over time, more parts of the brain are damaged. As this happens, more symptoms develop. They also become more severe.

Gum disease is caused by specific types of bacteria that coat teeth and cause gums to bleed. The coating is called a “biofilm”. Research demonstrates a cause and effect relationship between gum disease and worsening memory as dental treatment for gum disease in Alzheimer’s disease patients appears to improve memory. However, the relevance of this observation remains to be fully investigated.

A novel concept in which, bacterial infections of the brain have resulted in the cause of Alzheimer’s disease is being suggested. This hypothesis proposes the ‘plaques’ of Alzheimer’s disease as a biofilm containing multiple types of bacteria living together harmoniously. Our interest in this project comes from our expertise in the oral-infection model of Alzheimer’s disease and from two recent research articles that focused on non-oral bacterial biofilm found within the plaques. Since bacteria responsible for causing gum disease are found in late-onset Alzheimer’s disease brains; there is a high possibility that they are likely to be found in the plaque biofilm as well. We propose to explore this novel concept further to identify specific oral bacteria and their contribution to AD plaques in archival tissue specimens from Syphilis with Alzheimer’s disease diagnosis cases, as this disease is caused by bacteria from the same ‘family’.

Project status: Closed

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