Advancing the investigation of cortical brain organoids to unravel the mechanisms of neurodegenerative diseases

Neurodegenerative Diseases (NDDs), including Alzheimer's (AD) and Parkinson's (PD), are increasingly prevalent, primarily due to the aging population. These conditions affect millions and present complex pathological characteristics such as Amyloid-B (AB) plaques and tau protein neurofibrillary tangles (NFT) for AD. Current animal models fail to adequately represent human-specific intricacies, leading to challenges in understanding NDDs and an urgent need for more advanced research models. This research proposal aims to improve our understanding of cortical organoid models through the development and optimization of novel optical and electrophysiological techniques to study molecular mechanisms in three-dimensional cultures. The combination of the two modalities will allow for structural and electrical characterization of organoid development and internal mechanisms. The initial part of the project will focus on training and exploring advanced optical and electrophysiological methods to establish a solid foundation in organoid characterization. Techniques, including structured illumination microscopy and light-sheet fluorescence microscopy, will be evaluated for their potential to provide high-resolution and reduced phototoxicity. These methods will then be validated into a comprehensive organoid analysis pipeline incorporating custom hardware and software to manage and analyze large amounts of images and electrophysiological data. Finally, the last part of the project will leverage the platform to investigate molecular mechanisms underlying NDDs, focusing on tracking tau protein dynamics and stress pathways in cortical organoids. The combination of these imaging modalities and a multidisciplinary approach will offer new methods of characterizing and studying the pathophysiology of NDDs.