Mechanisms of Early Tau Seeding in Alzheimer’s Disease

About the Project

We are recruiting a PhD student to work on a 3.5 year multidisciplinary project withing the Departments of Brain Sciences and Chemistry at Imperial College London investigating early tau aggregation and propagation in Alzheimer’s disease. The student’s supervisors will be Clin Ass Prof Javier Alegre-Abarrategui, Prof Nicholas Mazarakis and Dr Francesco Aprile. The project is funded by the Alzheimer’s Research UK.

Using tau proximity ligation (tau-PLA) in post-mortem human brain, we identified early tau aggregates with seeding activity associated with widespread single-nucleus transcriptomic dysregulation across neurons and glia [1, 2]. Upregulated genes, including APP, MAPT, and PSEN1, were enriched for AD heritability, while pseudotime analysis linked the progression of tau pathology to astrocytic reactivity. The student’s project aims include defining seeding-competent soluble tau species in postmortem brain homogenates and test the role of APP, MAPT, and PSEN1 and another four genes upregulated in early stages of tau aggregation in astrocytes by silencing using siRNA and shRNA and measuring tau astrocyte-mediated uptake, intracellular seeding, and toxicity. The student will work alongside a newly recruited PDRA who will perform complementary work to the student’s aims including mapping cell-type and subcellular localisation of active tau seeding in situ; determining tau isoform-specific contributions; and establishing the relationship of tau seeding with Aβ species.

The student will work across the three supervisor’s laboratories at Imperial College London, with the possibility of visiting opportunities in the laboratory of Prof Tim Viney in Oxford, and will receive training across Neuropathology, Cell biology, Biochemistry and Advanced imaging.

Applicants should hold or expect to obtain a first or upper-second class honours degree or equivalent in the Biomedical Sciences, demonstrate strong interest in neuroscience / neurodegeneration, and demonstrate good communication and organisational skills. Applicants must also meet Imperial College’s English language requirements.

A Master’s degree in neuroscience / neurodegeneration related subject or equivalent and laboratory research experience in cell biology / molecular biology would be advantageous.