10 July 2020

The main challenge in testing Alzheimers drugs in clinical trials is that participants need to have symptoms. But once people have symptoms, it is usually too late for treatments to have a significant effect, as many brain cells have already died.

The only current way to test potential preventative treatments is by identifying participants who are at higher risk of developing Alzheimers and seeing if treatments prevent the onset of their disease. This includes people with Down's syndrome (DS) who have around a 70 per cent chance of developing Alzheimers during their lifetime. This is because the extra chromosome 21 they carry includes the gene for amyloid precursor protein which causes early Alzheimers when overdosed or mutated.

In the study, published in the Nature group journal Molecular Psychiatry, the researchers collected hair cells from people with DS and reprogrammed them to become stem cells, which were then directed to turn into brain cells in a dish.

In these brain-like cells, the researchers saw Alzheimers-like pathology develop rapidly, including the hallmark trio of signs of Alzheimers progression - amyloid plaque-like lesions, progressive neuronal death and abnormal accumulations of a protein called tau inside neurons.

Lead researcher Professor Dean Nietifrom Queen Mary's Blizard Institute commented: This work represents a remarkable achievement, as this is the first cell-based system that has the full trio of Alzheimers-pathologies, without any artificial gene overexpression. This system opens up the prospect for screening for new drugs aimed at delaying or even preventing Alzheimers before neuronal death starts.

The researchers showed that the system could be used as an early preventative-drug testing platform. They took two different drugs which are known to inhibit -amyloid production, tested them on these brain cells, and in six weeks showed that they prevented the onset of Alzheimers-pathology.

Although these two particular drugs have failed clinical trials for other reasons and therefore arent suitable treatments for Alzheimers, the team showed the proof-of-principle that the system can be used on any drug compound, and within six weeks show whether or not it has potential for further investigation.

The team also found proof of the existence of a naturally-functioning Alzheimers suppressor gene (BACE2 gene). Acting in a similar way to tumour suppressor genes in cancer, the increased activity of this gene contributes to the prevention/slowing down of Alzheimers in human brain tissue, and could in the future be used as a biomarker to determine peoples risk of developing the disease, or as a new therapeutic approach by boosting its action.

Professor Dean Nietiexplained: Although its still early days, the system raises a theoretical possibility for further development as a tool to predict who might develop Alzheimers. The same stem cell process could be used on anyones hair follicles, the resulting brain cells of which may or may not then develop Alzheimers-pathology in the dish. The idea would be to catch the people at higher risk of early disease in a cell-based system, before it starts in a persons brain, and allow for the possibilities of individualised preventive interventions. We are still a long way from reaching this goal.

Co-author Professor John Hardy from UCL added: I think we have the potential now to develop a new, human model of the disease which would be a great step forward.

The discoveries in this study were dependent on contributions from people with DS who kindly accepted to participate in this study, the results of which could be beneficial for people with and without DS in preventing Alzheimers. The Downs Syndrome Association (UK) provided essential support and help with recruitment of the participants in the study.

Carol Boys, Chief Executive of the Downs Syndrome Association, said: These are exciting results from an extremely eminent group of researchers and another small step towards a possible intervention and treatment for Alzheimers Disease. The Downs Syndrome Association is delighted to have been able to support this brilliant work.

The main funders of the project were Wellcome (UK) and National Medical Research Council (Singapore), and involved major contributions from the Nanyang Technological University Singapore, UCL (Prof. John Hardy and Prof. Henrik Zetterberg) and Sahlgrenska Academy of the University of Gothenburg, Sweden (Prof. Henrik Zetterberg), as well as a number of international partners, including The Croatian Institute for Brain Research at the University of Zagreb Medical School.

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SMD - Scientists discover protective Alzheimer's gene and develop rapid drug-testing platform - QMUL