1st Supervisor: Dr Antonios N. Pouliopoulos, King’s College London
2nd Supervisor: Dr Michelle Ma, King’s College London
Clinical Supervisor: Prof Alexander Hammers, King’s College London
Aim of the PhD Project:
Acoustically deliver radiolabelled anti-tau antibodies into the brain for simultaneous diagnosis and treatment of Alzheimer’s disease (AD).
- Label antibodies with 89Zr for PET imaging
- Deliver antibodies with ultrasound across the blood-brain barrier of WT and AD mice
- Measure tau load and behavioural impact over time following treatment
Lay Summary:
Alzheimer’s disease is a debilitating neurodegenerative disease with a formidable societal burden, which is constantly increasing. The gradual accumulation of two proteins, called amyloid and tau, in the brain is considered to be the molecular hallmark of Alzheimer’s. Current methods for diagnosing Alzheimer’s include amyloid detection through either invasive techniques or medical imaging. However, amyloid accumulation occurs throughout the brain and is not directly related to symptom onset. Furthermore, multiple clinical trials focused on amyloid reduction have not improved the condition of Alzheimer’s patients.
On the other hand, tau proteins are typically detected within brain areas affected by Alzheimer’s. Additionally, tau accumulation is directly related to symptom worsening, likely due to the presence of both extracellular and intracellular tangles which correlate with neuronal depletion and cognitive decline. In this project, we aim to “light up” tau and follow its accumulation and/or clearance over time in a mouse model of Alzheimer’s. We will develop antibodies targeting tau, which will be detectable with PET imaging. Antibodies typically have a poor penetration profile across the blood-brain barrier, which protects our brain from pathogens in the blood. The combined use of focused ultrasound and microbubbles can overcome the blood-brain barrier in a non-invasive and localized way. We will deliver labelled antibodies into brain regions related to memory (e.g., hippocampus), and evaluate the amount of tau proteins over time.
At the same time, ultrasound treatments can reduce the amount of amyloid and tau, even without drug administration. Additionally, ultrasound treatments may lead to behavioural improvement in both healthy and Alzheimer’s mice. Here, we will investigate the clearance rate of tau through serial PET imaging of labelled antibodies. We hypothesize that the combined action of ultrasound-triggered immune response and antibody-based immunotherapy will have a therapeutic effect, by either delaying or even halting tau accumulation and symptom deterioration. The latter will be tested with behavioural tests of memory-impaired Alzheimer’s mice. Therefore, the second aim of this project will be to establish the therapeutic effect of delivering tau antibodies using ultrasound.
The prospective candidate is expected to have a background in biomedical engineering, imaging chemistry/biology, biochemistry, physics, biology or a related STEM field. The successful candidate will be trained in radio-chemistry, therapeutic ultrasound, and in vivo experiments.
Lighting up tau. 89Zr4+-labelled anti-tau antibodies will be delivered across the blood-brain barrier using focused ultrasound, to detect and clear tau tangles in Alzheimer’s disease