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Nanoscale dynamics in the extracellular space of the brain in vivo

Periodic Reporting for period 3 - BrainNanoFlow (Nanoscale dynamics in the extracellular space of the brain in vivo)

Reporting period: 2021-12-01 to 2023-05-31

Evidence suggests that aggregates of proteins such as amyloid-beta play a key role in neurodegeneration, directly inducing toxic effects and acting as seeds to propagate the disease in the brain. A large fraction of these aggregates circulate the space in between brain cells and need to be constantly cleared from this narrow and complex space. The clearance mechanisms by which this extracellular "waste" is removed from the brain are not fully understood, as much of the dynamics happens at very small spatial scales and changes between wake and sleep. The project aims to develop tools to study the extracellular clearance of protein aggregates using a combination of nanotechnology tools and high-resolution microscopy. This will have a deep impact in our understanding of clearance mechanisms in the brain and the mechanisms by which protein aggregates induce toxicity in the brain. In turn, the understanding of these mechanisms will give us better tools to fight against dementia.
The first period of the project largely focused on the development of the biophysical methods needed to address the biological questions. We have worked on tools to characterise protein aggregates at the single-molecule level, and worked on tools to study the interactions between this aggregates and receptors at the membrane of neurones. Furthermore, we have studied some of the regulatory mechanisms of fluid clearance from the extracellular space of the brain in biological models of different complexities, ranging from dissociated cells in culture to living animals.
The most important achievement is the tracking of individual nanoparticles in the brain of living anaesthetised animals. This will allow us to test the so-called "glymphatic hypothesis" at the nanoscale before the end of the project, which will be a major breakthrough in neuroscience.