Treating Alzheimer's disease by characterising and repairing circuit activity using GENUS therapy

Alzheimer’s disease (AD) is a neurodegenerative disease for which there is no cure. Decades of research have revealed the unique genetic, molecular and cellular pathology of AD. However, largely due to a lack of techniques enabling the precise measurement of neural circuit activity in vivo, we know little about how it affects the high-level processing that underlies cognitive functions such as memory and spatial navigation. To address this gap in knowledge, our first aim is to capitalize on recent technical developments in our labs to measure activity of thousands of neurons simultaneously in AD mice that are trained to perform a cognitive task. We will focus on a cortical area called the retrosplenial cortex (RSC), a key brain structure for memory and navigation and an early target of AD. A second aim is to test and further develop a novel and highly-promising therapy that significantly improves memory in mouse models of the disease. By presenting multisensory stimuli (visual and auditory) at 40 Hz to restore gamma oscillations in the cortex, this therapy (acronym: GENUS) reduces extracellular peptide aggregates and significantly improves cognition. We will use this therapy to test whether the improvements in cognition are mirrored by a restoration of relevant microcircuit function in RSC. A third major aim is to develop a new device, called GAMMAHEAL, to dynamically optimise the multisensory stimuli by using real-time feedback information from cortical rhythms. We will apply this closed-loop stimulation platform in mice and humans, and develop it such that, at project completion, it is ready to be applied in human AD patients.

Main objective of the project:

  • The project aims to unravel the mechanisms by which Alzheimer’s disease affects key circuit function in the brain and how the GENUS therapy can be used and optimized to restore normal circuit dynamics in both animal models of the disease and in humans.

Expected results:

  • The project will lead to a better understanding of how Alzheimer’s disease affects key brain structures, especially the retrosplenial cortex. Moreover, the project will lead to a personalized therapy called GAMMAHEAL, which is based on multisensory closed-loop GENUS stimulation. GAMMAHEAL promises to offer an efficient solution for restoring normal neural circuit dynamics enabling the efficient treatment of Alzheimer’s disease patients.