Uncovering the molecular mechanism of the amyloid cascade
Despite the regrettable failure of several -amyloid (A) based therapies to show benefit for the disease, A is still widely held to be the causative agent of Alzheimer’s disease. The major objective of this project was to obtain a better understanding of the molecular processes activated by A that drive Alzheimer’s disease. The aim being to identify novel, tractable therapeutic targets against which drugs can be developed to effectively combat the disease.
This project has now been completed and the data we generated during it, along with accumulating evidence from others, strongly supports our view that the wnt-Planar Cell Polarity (wnt-PCP) pathway is an important mediator of many important aspects of A neurotoxicity. This project has progressed our understanding of the Alzheimer’s disease process at the molecular level, particularly in regard of the synaptic effects of A. It has thus strengthened the case for the continued investigation of the A induced wnt-PCP pathway as it will most certainly increase our understanding of the disease further and identify useful novel therapeutic targets. In the interim this pathway-driven approach has uncovered three good candidate classes of drugs for further evaluation for repurposing for Alzheimer’s disease.
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 remain enigmatic. A crucial gap in our understanding is the basic cause of the disease, or specifically the link between senile plaques (composed of -amyloid) and neurofibrilary tangles (formed from hyperphophosphorylated tau protein). In some way A is believed to cause tangle formation to occur 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, and was first put forward by Hardy and Higgins in 1992. If we could understand the mechanism through which A causes this to happen we would have a better idea about the mechanism of the disease, which would put us in a much better position to then find ways to attack it.
We believe we have, at last, begun to uncover the sequence of events A sets into motion, which result in the damaging effects upon tau and also the effects of A on the connections between neurons, the synapses, that then lead to dementia.
How was the research carried out?
We used several different approaches in the study. Our main working model being rat primary neuronal cultures with measures taken of endogenous gene expression levels by qRT-PCR and levels, activation states and subcellular localisation of pathway component and pathway target proteins by immunoblotting and immunocytochemistry. We also examined genes and proteins in mouse, rat and human brain tissue samples and also used bioinformatic approaches and large publicly available data sets of Alzheimer’s disease brain transcriptomic data.
More recently we have begun using confocal microscopy to measure synaptic morphology following A and Dkk1 treatments.
Where did it happening?
Work was performed at the Institute of Psychiatry and with a number of collaborators in the UK.
Who was involved?
Dr Richard Killick, Dr Elena Ribe and Professor Simon Lovestone.
What was the timescale?
This was a three year project funded by the Alzheimer’s Society and BUPA.
The project was completed in March 2014.
To find out more
Dr Richard Killick