Alzheimer's Disease (AD), the most common form of dementia, is impacting healthcare in aging populations worldwide. It results from a cascade of pathological cellular events involving abnormal accumulation of amyloid beta protein, and downstream of this, the generation of tau protein aggregates within affected cells. Mouse models have been an important tool for understanding these processes and their affects on memory and cognition. However, this can require the breeding of large numbers of transgenic mice; in addition, mice do not naturally develop AD, and it has proved difficult to develop mouse models incorporating human genes which include all aspects of AD. 3D organoid models based on human cell lines offer the prospect of drastically reducing mouse usage, while increase relevance to human disease states.
The aim of this project is to transfer the know-how and technology necessary to successfully establish organoids from the Lancaster (MRC LMB) and Wray (UCL) groups to the Schultz group at Imperial College. The Lancaster group have made key contributions to the development of cerebral organoids, and the Wray group have been at the forefront of efforts to make organoid models of neurodegenerative disease processes, making them ideal project partners. This will enable the Schultz laboratory to substantially reduce mouse usage, while contributing to research on ending neurodegenerative disease conditions. We will (using this acquired knowledge) establish cerebral organoid models, transduce them with a genetically encoded calcium indicator, and demonstrate that multiphoton calcium imaging can be used with neural manifold analyses to characterise system dynamics, as has been achieved with in vivo mouse neuroimaging data. We will then generate cerebral organoids from induced pluripotent stem cells incorporating tau splicing mutations, and study the progression of changes in neural circuit dynamics using multiphoton microscopy.