Dr Claire Durrant: Locked-out of the lab: time to think?

The full publication of Claire’s paper published with Tara Spires-Jones and PHD student Sarah Kent can be found at https://link.springer.com/article/10.1007/s00401-020-02196-w.

When you look inside the brain of someone who died from Alzheimer’s disease, it can be likened to examining a crime scene. The damage may be obvious, but what caused it, and how? Are we missing any important clues?

In Alzheimer’s disease, we know that nerve cells, and the connections between them which allow them to communicate (synapses), are gradually destroyed as the disease progresses. The path of destruction starts off in parts of the brain responsible for short-term memory, explaining why people living with Alzheimer’s disease can be forgetful, or get lost easily. As the disease progresses, this damage spreads throughout the brain, resulting in a wide-range of symptoms including changes to vision, movement and speech. Whilst the key victims (nerve cells and synapses) are clear, identifying the culprits is more complex.  For many years, focus has been on two proteins, amyloid-beta (Aβ) and tau, which form large, sticky aggregates inside the brain of people with Alzheimer’s disease. Aggregates of tau and Aβ can damage nerve cells and synapses in experiments, so research has focused on targeting these proteins when looking to design new drugs.

The involvement of Aβ and tau in Alzheimer’s disease, however, appears to be more complex than originally thought. Both proteins are naturally present throughout the body in humans and other animals. A tau-like gene has been found in lampreys (eel-like fish) and sharks, whilst Aβ-like sequences are found in sea anemones, meaning these proteins have been in existence for over 550 million years. Why would purely toxic proteins be kept through millions of years of evolution if they didn’t also serve important biological processes?

When the world went into lockdown, Dr Claire Durrant, RAD fellow at the University of Edinburgh, alongside Prof. Tara Spires-Jones and PhD student Sarah Kent, took the opportunity to step back and consolidate what we know about tau and Aβ. They read hundreds of scientific publications, spanning decades of research, and summarised their findings in a review article, now published in the neuroscience journal Acta Neuropathologica. The work suggests that the villains in Alzheimer’s disease have a back story: tau and Aβ are not “born evil”. In fact, throughout life, they play a diverse range of important roles, from protecting DNA from damage to aiding memory formation. This has important implications for understanding, and hopefully one day treating, Alzheimer’s disease. It is likely that the clumping of tau and Aβ that occurs in Alzheimer’s disease not only turns these proteins toxic, but also reduces their ability to perform their normal roles. Future therapies that balance disarming toxicity and restoring normality may therefore have a stronger chance at success. The more research we do, the greater the chance we have of finding the winning combination.