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Uncovering the molecular mechanism of the amyloid cascade


We have identified part of the mechanism by which the toxic agent of Alzheimer’s disease, b-amyloid, acts. We now wish to build upon this novel and long needed finding to further dissect the molecular mechanism that underlies Alzheimer’s disease pathology. A central element in the path is the tumour suppressor protein, p53. We are now funded to further unravel the molecular pathway, a task which we believe will be aided by the massive amount of research and knowledge already in place regarding p53 and it role in cancer.

Why carry out the research?

A great deal is known about Alzheimer’s disease, whilst at the same time some very important things about the disease remian enigmatic. A crucial gap in our understanding is the basic cause of the disease, or specifically the link between senile plaques (made of b-amyloid) and neurofibrilary tangles (made of hyperphophosphorylated tau). b-amyloid (Ab) is believed to cause the tangles and it is the tangles (or more likely toxic soluble forms of tau) which then kill neurons and damage the brain. This concept, widely accepted by the field, is known as the amyloid cascade hypothesis, first put forward by Hardy and Higgins in 1992. If we learn how Ab makes this happen we would know the underlying mechanism of the disease and this would put us in a much better position to then attempt treat it.

We believe we have, at last, begun to uncover the sequence of events Ab sets into motion, which result in the damaging effects upon tau that then lead to dementia..

How is the research being undertaken?

We have uncovered a considerable part of the “amyloid cascade” pathway, we know Ab acts via the upregualtion of p53, albeit in a quite specific way, to selectively drive DKK1 expression. We know DKK1 then drives wnt signalling down the planar cell polarity pathway to drive gene expression via JNK1. We have identified a set of Ab/DKK1 signature genes, two of which we have shown mediate Ab toxicity, and one of which may well be a driver of increased tau phosphorylation. There still remain many gaps in the pathway. However, we can now manipulate this skeleton pathway at different levels and begin to fill in these gaps. We believe in this way we will derive a complete pathway from Ab to tau and toxicity, which may be linear, but more likely will also have several branch points and route to tau and other aspects of Alzheimer’s pathology.

We use cellular and molecular biology techniques. Nerve cells are grown in culture dishes; specific elements in the pathway are manipulated; measurements are then taken of genes and proteins relevant to Alzheimer’s disease and of components in the pathway. As we discover more steps in the pathway we will confirm them by performing experiments in rat hippocampal brain slices, which more closely represent the intact brain. Finally, we will then check findings by examining each component of the pathway in human post mortem brain samples.

Where is it happening?

At the Institute of Psychiatry and with a number of collaborators in the UK, Europe and the USA.

Who is involved?

Dr Richard Killick, Dr Elena Ribe and Professor Simon Lovestone.

What is the timescale?

Three year project funded by the Alzheimer’s Society and BUPA.

To find out more

Please contact:-

Dr Richard Killick

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