Clinical Supervisor: Professor 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.
Project description/background: Alzheimer’s disease (AD) is a debilitating neurodegenerative pathology with a formidable societal burden, which is constantly increasing. The gradual accumulation of amyloid and tau is considered to be the molecular hallmark of AD. Current methods for confirming the AD diagnosis include amyloid detection through either a lumbar puncture or amyloid PET imaging. However, amyloid accumulation occurs throughout the brain and is not temporally proximal to symptom onset. Furthermore, multiple clinical trials focused on amyloid reduction have not signalled a breakthrough in terms of treatment outcomes. On the other hand, tau tangles are typically detected within brain areas affected by AD. 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 murine AD model. We will develop 89Zr-labelled IgG antibodies targeting phosphorylated tau. 89Zr has a half-life of 3.1 days, which allows serial PET imaging for over a week. IgG antibodies typically have a poor penetration profile across the blood-brain barrier (BBB). The combined use of focused ultrasound (FUS) and microbubbles can overcome the BBB in a non-invasive and localized way. FUS-mediated delivery of 89Zr-labelled antibodies is hypothesized to increase the tracer uptake into the targeted brain areas. The primary pillar of this project is thus imaging of the tau load in AD-affected areas, such as the hippocampus, through the enhanced delivery of an IgG-based PET tracer in both wild-type and transgenic rTg4510 mice. At the same time, recent data suggest that acoustically-mediated BBB opening reduces both amyloid and tau in the brain of transgenic AD mice, even in the absence of an anti-amyloid or anti-tau drug. The proposed mechanism is based on an immune response triggered by this intervention, which entails albumin-mediated microglia activation and lysosomal activity or autophagy. The downstream trafficking and clearance mechanism of amyloid and tau is currently under investigation. Additionally, FUS treatments trigger neurogenesis and angiogenesis, leading to behavioural improvement in both wild-type and transgenic rodents, compared to pre-FUS. Here, we will investigate the clearance rate and route of tau both at the short-term (hours) and the long-term (weeks), through serial PET imaging of 89Zr-labelled antibodies. We hypothesize that the combined action of FUS-triggered immune response and active binding of the IgG to phosphorylated tau will have a therapeutic effect, by either delaying or even halting tau accumulation and symptom deterioration. The latter will be tested with behavioural tests (e.g., Morris water maze) of memory-impaired rTg4510 transgenic mice. Therefore, the second pillar of this project will be to establish the therapeutic effect of delivering tau-binding antibodies using FUS. The prospective candidate is expected to have a background in biomedical engineering, imaging chemistry/biology, biochemistry, physics, biology or a related field. The successful candidate will be trained in radio-chemistry, therapeutic ultrasound, and in vivo experiments.