How are the connections between brain cells affected in Alzheimer's disease?

Read about a research project we funded into synaptic dysfunction in Alzheimer’s disease patient iPSC-derived cortical neurons harbouring mutations in APP or PSEN1.

Lead Investigator: Dr Richard Wade-Martins

Institution: University of Oxford

Grant type: PhD studentship

Duration: 3 years

Amount: £85,000

Why did we fund this project?

Comments from members of our Research Network:

'Would add to the sum of knowledge that we are building up to combat dementia.'

'Useful in furthering the understanding of communication between cells in the brain and the specific changes that prevent this happening.'

'It is exciting to see the latest advances in scientific technologies being used to take forward Alzheimer's disease research.'

What do we already know?

New stem cell technology has enabled the growth of human neurones (nerve cells) in the laboratory to study diseases, such as Alzheimer's disease. Recent studies using these human neurones with several different familial Alzheimer's disease genetic mutations have found that the neurones produce high levels of amyloid-beta, which forms plaques, a hallmark of Alzheimer's disease. They have also shown evidence of initial chemical changes in tau protein that forms tangles, another hallmark of Alzheimer's disease.

Synapses are specialised chemical communication junctions between neurones. Loss of synapses is the best correlate of cognitive decline, or failing memory, but before synapses are actually lost there are changes that prevent the synapse from functioning properly.

Synaptic plasticity describes the ability of neuronal communication to change in strength dependent on activity. The more two neurones communicate, the stronger their interactions. Synaptic plasticity is considered to be the cellular basis of memory.

Many studies in animal models have shown impairment of synaptic plasticity in mice that overproduce amyloid-beta, which is associated with a decrease in the ability to form memories. However, the researchers have previously found that this does not occur in mice that produce amyloid-beta but lack the tau protein, implying that crucial changes inside the cell involving tau are required for amyloid-beta to cause dysfunction.

What does this project involve?

In this project the researchers will take advantage of the latest stem cell technologies to grow human neurones derived from people with familial Alzheimer's disease and then systematically examine how communication between these neurones, when they are grown in the laboratory, is altered as a result of the disease process. The genetic mutations that they will study have been shown to produce high levels of amyloid-beta, and therefore they expect these neurones to have impaired synaptic plasticity.

The development of technologies that can convert adult human cells into stem cells is now making it possible to generate human neurones that were previously inaccessible without highly invasive procedures. The stem cells that are produced are known as induced pluripotent stem cells (iPSCs) and enable the study of a disease-relevant cell types that carry all the patient's own genes, including any Alzheimer's disease-causing variants.

There are several drugs that the researchers can apply to the neurones that can decrease the production of amyloid-beta, or change the chemical modifications of tau protein. They will apply these drugs and examine whether correct neuronal communication is restored. 

How will this benefit people with dementia?

The use of patient-derived iPSCs provides a relevant model of Alzheimer's disease and may uncover some disease processes that are not present in animal models. Synaptic dysfunction and subsequent synaptic loss is critical to memory impairment andcognitive decline. Further insights into the molecular mechanisms that disrupt neuronal communication may enable the development of novel drug treatments. This model also has the potential to be used to test the efficacy and toxicity of new drug treatments on human neurones.

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