Alzheimer’s and other forms of dementia are some of the biggest health problems currently facing developed countries. With ageing populations and cuts in spending on social care, I’m sure I’m not the only one who fears what the future may bring for myself or my loved ones.

And as a neuroscience and psychology presenter, I am often asked questions about this disease, so I try to keep up to date with the research. That’s why, when I spotted a talk on the topic at the Cambridge Science Festival last week, I decided to go along. The talk was by Professor Giovanna Mallucci, who is Associate Director of the UK Dementia Research Institute at the University of Cambridge, and covered her team’s fascinating work on the mechanisms underlying dementia, and how we might be able to intervene to prevent or even cure it.

Professor Giovanna Mallucci (Pic by Cambridge University)

For a long time, we have known that there is an association between Alzheimer’s disease and a build-up of misfolded proteins in the brain. There are two main types of protein involved- beta-Amyloid ‘plaques’ and Tau ‘tangles’, but scientists don’t know exactly how or why these cause the symptoms of dementia. And experiments to find out have produced some strange results- like the multitude of drugs developed to break down these plaques having no effect on symptoms[i]. So Mallucci’s group has been trying to understand the mechanism that might translate misfolded proteins into symptoms, and they’ve discovered something interesting.

In all our cells, we have a switch which can be triggered by a misfolded protein. When this problem is detected, the cell shuts down protein production briefly, to sort out the issue- a bit like turning a jammed printer off and on again. But in Alzheimer’s and related diseases, so much misfolded protein builds up that the switch gets stuck in the off mode, and the cell becomes unable to produce any proteins, potentially for weeks or longer. Brain cells need to produce proteins to hold themselves together and keep their synaptic connections functioning. If they are unable to make them, the synapses rapidly fall apart, and the neuron itself can die off. Mallucci believes that this is the neurodegeneration we see in dementia[ii].

Using mice bred to have a form of dementia, the researchers managed to pinpoint the molecular cascade that triggers this protein ‘off switch’, and so were able to intervene. Initially using genetic manipulation, and later drug therapy, they were able to not only prevent further degeneration in these mice, but even reverse some of the effects of the misfolded protein build ups, simply by shutting off this cascade and allowing protein production to resume[iii]. Amazingly, they appeared to have found a cure for a type of dementia, at least in mice[iv]. Other groups have since replicated these effects in other mouse models, suggesting a similar mechanism for different types of dementia.

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The next stage was to see if this finding would translate to humans, but there was one problem. Genetic manipulation was out, for obvious reasons, and unfortunately all the drugs she had found that affected the ‘off switch’ in mice were toxic to other parts of the body. So one of her students set about looking for an alternative. He searched databases of drugs that are currently in use and tested those that looked promising. And it paid off. The group found two drugs which affected this pathway- a licenced antidepressant and a cancer drug[v].  Because these are ‘repurposed’ drugs, they have already passed safety testing, so they can now skip straight to clinical trials. And Mallucci assured us that tests on the first Alzheimer’s patient will be beginning imminently.

If these drugs have a similar effect in humans as they did in mice, this could lead to a step change in our treatment of Alzheimer’s. Of course, we still have to be cautious- humans are very different to mice and there is always the possibility of unexpected side effects, or the drug working less well than hoped. But even if its effect is smaller, simply delaying the worsening of symptoms rather than reversing them, treatments like these could improve the lives of millions of people. And I think that’s a pretty exciting possibility.

[i] https://www.sciencemag.org/news/2019/03/another-major-drug-candidate-targeting-brain-plaques-alzheimer-s-disease-has-failed

[ii] https://academic.oup.com/brain/article/139/8/2113/1753665

[iii] https://www.nature.com/articles/cddis201549

[iv] https://www.nature.com/news/2007/070131/full/news070129-8.html

[v] https://www.cam.ac.uk/research/news/scientists-discover-two-repurposed-drugs-that-arrest-neurodegeneration-in-mice

Ginny Smith is a science presenter and writer. A Natural Sciences and Psychology graduate of Cambridge, Ginny performs science shows all over the world and presents a wide range of science content for the likes of the Cosmic Shambles Network and the Naked Scientists. She is the co-author of three DK Publishing books looking at science, food and the human body. She is @GinnyFBSmith on Twitter.

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