Dr Daniel Maddison was one of 17 early career researchers honoured by the Alzheimer’s Society this year. He has been awarded a Postdoctoral Fellowship and over the next three years will be working in the Avezov lab at UK Dementia Research Institute at Cambridge with the goal of developing new ways to see and clear toxic tau aggregates from the brain.

We spoke to Daniel about his research project, the technologies he hopes to use and what he hopes to uncover.

What can you tell us about your research project?

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My research takes a proactive approach to fighting dementia by tackling the disease early, right inside our brain cells. Instead of waiting for damage to occur, my goal is to find ways to boost the brain’s natural "clean-up crew"—a sophisticated quality control system called proteostasis—to clear away harmful protein clumps before they can cause widespread damage.

To watch and manipulate this clean-up process, I use several cutting-edge tools:

• i3Neurons: Living brain cells that we grow in the lab from human stem cells.
• Tau-Specific Molecular Probes & FLIM: I have developed special molecular sensors that light up specifically when the tau protein starts clumping together. These toxic tau aggregates are a key driving feature of Alzheimer's disease, Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), and Corticobasal Degeneration (CBD). Using Fluorescence Lifetime Imaging Microscopy (FLIM), I can make videos of these tau clumps forming and being cleared away inside living cells.
• Mass Spectrometry: This technique allows me to take a detailed inventory of the exact proteins involved in the clean-up crew that surrounds the tau clumps and breaks them up.
• Drug Discovery Platform: I am rebuilding this clean-up system in a test tube so I can rapidly test thousands of potential drugs directly on different types of tau clumps. In our lab we are using both conventional high-throughput and novel, AI-guided approaches to finding the right drug. 

What do you hope to uncover through this work?

I want to identify the specific key proteins that act as the cellular "on switch" for breaking up these toxic tau aggregates.

By understanding how to flip this switch on demand, my goal is to move from fundamental discovery to having a ready-to-use drug screening platform by the end of my three-year fellowship.

How do you hope this will help patients?

Because tau pathology is central to so many conditions, I hope this leads to a new class of therapies that can delay, slow down, or even completely stop Alzheimer's and other tau-related dementias before they take hold, vastly improving the quality of life for millions.