University of Exeter Archives - BRACE Alzheimer's Research

BRACE awards funding for an important Alzheimer’s disease pilot study at the University of Exeter

Nikola Scanlon — Thu, 06 May 2021 09:32:37 +0000

The grant from BRACE to the Living Systems Institute group at Exeter is part of the charity’s acclaimed pilot scheme which pursues new and promising lines of research.

This award will fund important research into cell communication and its degeneration relating to Alzheimer’s disease under the direction of Dr Steffen Scholpp, Associate Professor Cell and Developmental Biology.

One of the hallmarks of Alzheimer’s disease is abnormal accumulation of β-amyloid protein in the brain. It manifests itself as clumps of insoluble protein called plaques, but it is also present in a soluble form and it is believed high concentrations of this soluble β-amyloid is toxic to synapses. (Synapses act as a junction to transfer information between neurons in the brain).

The mechanism of this toxicity, however, is not known.

Professor Scholpp believes the explanation is that the abnormally high amounts of β-amyloid around the nerve cells disrupt the WNT sub-pathways, (WNT regulates many aspects of synapses in the brain), resulting in loss of synapses and, consequently, brain function.

It is this hypothesis that forms the basis of this pilot project and if correct the findings will lay the groundwork for far more effective treatments for Alzheimer’s disease.

Professor Scholpp said,

"BRACE does incredibly important work in this area and we feel privileged to be a part of it. We are hopeful that success within this project may attract much needed additional resources directed to breakthrough discoveries relating to dementia-related diseases."

BRACE Chief Executive Mark Poarch commented:

"The University of Exeter has an ambitious and important programme of dementia research, and BRACE is proud to have supported several of its projects, the latest being Professor Scholpp’s. The rapid development of COVID vaccines has shown what can be achieved when humanity is sufficiently determined to combat a health threat, and we must do all we can to ensure that dementia researchers are similarly equipped with the resources they need."

The post BRACE awards funding for an important Alzheimer’s disease pilot study at the University of Exeter appeared first on BRACE Alzheimer's Research.

Professor Steffen Scholpp – University of Exeter

Emma Bone — Mon, 21 Dec 2020 07:51:00 +0000

Professor Steffen Scholpp

Pilot Project: Started 2020

University of Exeter

Striking the right balance - WNT signalling in Alzheimer's disease.

See glossary at bottom of page for definition of underlined words.

Summary

A neuron in the brain is connected to hundreds of other neurons by as many as 10,000 connection points, known as synapses. These synapses serve as points of communication between the neurons. The capacity of the brain to form new synapses and prune others throughout our lifetime is the basis of learning and memory. These changes in neuronal connections are known as synaptic plasticity.

What do we already know?

Cell signalling, where crucial signals are passed from cell to cell, governs the necessary activities of neurons and coordinates multiple cellular actions. One of these signals known as WNT - regulates many aspects of synapses during brain development and in the adult brain. WNT signals increase the number, the density, and the strength of many synapses.

Alzheimer’s disease (AD) is primarily due to the loss of synaptic connections between neurons in the brain. Synapse loss leads to deterioration in memory and cognitive ability. Molecularly, we know of two significant changes in the diseased brain. Firstly, WNT is strongly decreased in AD brains, and therefore synaptic stability is reduced. Secondly, β-amyloid - a small molecule essential for controlling appropriate synaptic pruning - accumulates in the brain tissue.

What is this project trying to find out?

In this project, Prof Steffen Scholpp and his research team will test how WNT and β-amyloid interact in neurons. The researchers hypothesise that WNT signalling regulates the maintenance and growth of synaptic connections. In contrast, β-amyloid is required for pruning of unnecessary synapses. The research team will image the formation and disassembly of synaptic connections to test if WNT and β-amyloid keep a delicate balance between synaptic plasticity and synaptic stability - a step towards an understanding of the underlying molecular mechanism in AD.

Glossary

Gene – A gene is a region of DNA responsible for production of a protein.
Expression (of genes) – Expression of a gene involves the ‘turning on’ of the production of the relevant protein.
DNA Sequence – The precise ordering of the bases from which DNA is composed.
Epigenetic changes – Changes in the production of a protein that DO NOT involve changes in the DNA sequence.
Autopsy examination – an examination of a body after death to determine the cause of death or the character and extent of changes produced by disease.
Control Group – A control group in a scientific experiment is a group separated from the rest of the experiment, where the independent variable being tested cannot influence the results. In this case, the control group involves using brain tissue of people that did not have Alzheimers disease.

Further information

Please click here to find out more about dementia research at Exeter

Please click here for more information about the work of Adam Smith.

Please click here for more information about the work of Dr Katie Lunnon.

Please click here for more information about the work of Professor Jonathan Mill.

Share this page

The post Professor Steffen Scholpp – University of Exeter appeared first on BRACE Alzheimer's Research.

Dr Talitha Kerrigan – University of Exeter

admin — Mon, 07 Mar 2016 11:00:00 +0000

Dr Talitha Kerrigan

Pilot Project: University of Exeter, 2016

Amyloid β clearance and neuronal function in a human model of Alzheimer's Disease

Type of project: Pilot project

What do we already know?

Build-up of the protein amyloid-beta in brain cells leads to dysfunction in their signalling, which can impair the integrity of circuits within the brain and cause cognitive failure. Normally, the production and clearance of amyloid-beta in the brain is balanced, however in Alzheimer’s disease the mechanisms of clearance are substantially reduced resulting in an abnormal accumulation of the protein.

A major mechanism for amyloid-beta clearance is through break-down by an enzyme called Neprilysin (NEP). NEP is therefore thought to be protective to brain cells against the toxicity caused by amyloid-beta build-up and may have therapeutic benefit to Alzheimer’s disease and other dementias.

What is this project trying to find out?

While NEP in known to break-down amyloid beta its role in the communication between neurons has not yet been explored. The project will look at the link between the processing of amyloid precursor protein (APP) from which amyloid-beta is produced, the activity of NEP, and nerve cell communication via electrical signals.

How will they do this?

This project study human nerve cells which have been reprogrammed from the skin cells of patients with familial Alzheimer’s disease. These cells carry a mutation in preselin-1, a protein which processes APP cutting it to generate amyloid-beta. The expression of NEP in populations of nerves cells with different levels of APP processing will be compared and the resulting outcome on the cells physiology examined.

Genetic and pharmacological manipulations to enhance NEP activity will be employed to measure any resultant changes in amyloid-beta levels over time. This approach will also be used to establish if changing NEP alters communication and network connectivity within the nerve cell population.

Why is it important?

The project will provide a greater understanding of how nerve cell signals are disrupted during dementia. This study will provide important information required for the development of a novel therapeutic approach using NEP as a target for drugs against Alzheimer’s disease and other dementias.

Further information

Please click here for more information about the work of Dr Talitha Kerrigan

Share this page

The post Dr Talitha Kerrigan – University of Exeter appeared first on BRACE Alzheimer's Research.

Dr Katie Lunnon – University of Exeter

admin — Fri, 16 May 2014 11:58:00 +0000

Dr Katie Lunnon

PhD: University of Exeter, 2014

Exploring the role of epigenetic changes in Alzheimer’s disease

See glossary at bottom of page for definition of underlined words.

Summary

The ANK1 gene has been shown to undergo modification in the regions of the brain that typically show degradation due to Alzheimer’s disease (AD). This work will seek to understand the specific region of ANK1 which undergoes change, what effect this change has on the working of the cell and the effect of stopping this modification on the cell-based model. This work will help understand how AD targets specific regions of the brain and potentially provide new therapeutic drug targets for the control of AD.

What do we already know?

Expression of genes relies on a person’s DNA sequence, but an extra level of information is provided by epigenetics. Epigenetic modifications involve chemical tags which are able to turn genes on and off, and can be influenced by the environment that cells are in.

It has been found by this research group that a region of the gene known as ANK1 has a higher level of epigenetic modification in the brains of those with Alzheimer’s disease than those without. This is seen in regions associated with the disease, but not in regions which are generally unaffected or in blood samples taken from the patients during their lifetime. This may explain why some regions of the brain are affected more severely by Alzheimer’s disease while others remain relatively resistant to this damage.

What is this project trying to find out?

This project will look at the extent and location of epigenetic changes of the ANK1 gene in Alzheimer’s disease. This information will then be related to expression levels of the gene and the degree of Alzheimer’s disease as judged from autopsy examination.

How will they do this?

Molecular biology techniques will be used to assess the extent and location of epigenetic changes across the ANK1 gene in post-mortem Alzheimer’s disease brain tissue compared to controls. The abundance of ANK1 products will also be measured. This information will be related to the degree of disease progression to see if there is any relationship. Epigenetic editing techniques will be used to reverse the epigenetic changes in cell model experiments and see the effects this has on the properties of the cell.

Why is it important?

Epigenetic changes are potentially reversible, so identifying pathological epigenetic changes of ANK1 may help to identify new drug targets for Alzheimer’s disease.

Glossary

Further information

Please click here to find out more about dementia research at Exeter

Please click here for more information about the work of Adam Smith.

Please click here for more information about the work of Dr Katie Lunnon.

Please click here for more information about the work of Professor Jonathan Mill.

Share this page

The post Dr Katie Lunnon – University of Exeter appeared first on BRACE Alzheimer's Research.