Duff Lab

Understanding and finding treatments for Alzheimer's and frontotemporal dementia

The Duff Lab focuses on understanding and finding treatments for Alzheimer's disease (AD) and frontotemporal dementia (FTD), which are both linked to harmful changes in a protein called tau. These changes, known as tauopathies, cause damage in the brain and lead to dementia.

The programme has four key goals:

• Understanding genetics: Researchers are studying how genes affect the development of tau-related brain damage. This could help doctors predict how a patient's disease will progress and tailor treatments accordingly.
• Stopping disease spread: The team is investigating how tau-related damage spreads in the brain and looking for ways to stop this process before it leads to severe symptoms like memory loss.
• Protecting vulnerable brain cells: Some brain cells are more prone to damage from tau. The researchers are trying to understand why this happens and how to protect these vulnerable cells.
• Early treatment options: The team is exploring new treatments, including brain stimulation techniques, to intervene in the earliest stages of these diseases, potentially slowing or even reversing their progression.

This work is part of a larger effort to better understand and ultimately cure or prevent dementia.

The molecular causes and consequences of tauopathy in Alzheimer's disease and frontotemporal dementia

The "Pathological tau in AD and FTD" research programme, led by Karen Duff, focuses on uncovering the mechanisms and therapeutic opportunities related to tauopathies - neurodegenerative conditions characterised by tau protein aggregates. These tauopathies are significant contributors to dementia, including Alzheimer's disease (AD) and frontotemporal dementia (FTD).

The programme is organised around four main objectives:

1. Identifying genetic modifiers: This objective aims to discover genetic factors that influence the development and progression of tauopathies. Understanding these genetic influences can improve the prediction of clinical outcomes and allow for more personalized treatments. The research examines how genetic variants affect tau pathology distribution in diseases like progressive supranuclear palsy (PSP) and the cognitive decline associated with tauopathies. Current work focuses on the E3 ligase TRIM11, and identifying new genetic modifiers using the BXD genetic variant lines from Jax. A large NIH grant will support this research.
2. Mechanisms of tauopathy propagation: This objective explores how tauopathies spread within the brain and seeks therapeutic strategies to halt this progression. Key areas of investigation include the movement of tau proteins between neurons, particularly through extracellular vesicles, and the role of cellular mechanisms like proteostasis (protein homeostasis) in tau propagation. New mouse models are being developed to better understand these processes. The first manuscript describing tau KI mice is accepted (Nature Neuroscience). A manuscript describing cryoET structures of tau in extracellular vesicles is accepted (Nature Neuroscience) 
3. Selective cellular vulnerability: This objective focuses on why certain types of neurons are more vulnerable to tauopathies. Using advanced techniques such as spatial transcriptomics and proteomics, the research profiles vulnerable neurons and identifies molecular pathways that could be targeted therapeutically. The goal is to understand why excitatory neurons are more prone to tau pathology and to develop protective strategies. Spatial transcriptomics protocols have been optimised and are being used on mouse models. Single cell spatial proteomics is being optimized.
4. Therapeutic interventions in early disease stages: The final objective involves identifying and testing therapies effective in the earliest stages of tauopathies. This includes exploring neuromodulation techniques, such as Temporal Interference (TI), to correct network imbalances caused by tau pathology and potentially slow or reverse disease progression. Work on this is ongoing with Prof Nir Grossman.

The programme is highly collaborative, involving partnerships within UK DRI and globally, leveraging cutting-edge technologies to advance the understanding and treatment of tau-related dementias.