Cerebral organoid models for optical investigation of neural circuit dynamics in neurodegenerative diseases

Alzheimer's Disease (AD) is the most common form of dementia, and is having an increasing impact on healthcare in aging populations worldwide. It results from a cascade of pathological events involving accumulation of amyloid protein into extracellular plaques and the generation of tau protein aggregates within affected cells. To understand these processes, and how they affect the functioning of neural circuits underlying memory and cognition, mouse models have been important tool. However, they have drawbacks - as well as requiring the breeding and use of large numbers of mice, mice do not naturally develop AD, and it has proved difficult to develop mouse models incorporating human genes which include all necessary aspects of AD. 3D organoid models offer an attractive proposition which might drastically reduce the need for mouse usage, while, being based on human cell lines, increase the relevance of the models to human disease states.

The aim of this project is to transfer knowledge and skills from two laboratories which are currently performing research on cerebral organoid models to the Schultz laboratory, who currently work with in vivo mouse models of AD. Cerebral organoid technology will be transferred from the laboratories of Madeline Lancaster, who has been a key contributor to the development of cerebral organoids, and Selina Wray, who has been at the forefront of recent efforts to make cerebral organoid models of neurodegenerative disease processes. This will enable the Schultz laboratory to substantially reduce mouse usage, while contributing to research on ending debilitating neurodegenerative disease conditions. The cerebral organoid technology offers substantial potential for advancing the field - for instance through the development of models from patient-derived stem cells which can personalise medicine - if it can be disseminated to a wider range of the neuroscience community.

As well as reducing animal usage, cerebral organoid technology offers substantial potential for advancing neurodegenerative disease research - for instance through the development of models from patient-derived stem cells, leading to advances in personalized medicine. Such advances however require the dissemination of the organoid technology to a wider range of laboratories, including those involved in systems neuroscience research. This skills and technology transfer project will catalyze such dissemination, leading to advances in neuroscience and the development of therapeutics tailored to human genetics, while reducing the need for the use of animal disease models.

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.