Elucidating circuit disruptions in Alzheimer's disease

总结

Summary Alzheimer’s disease (AD) is the major cause of dementia currently without an effective cure. A number of clinical trial failures has been reported due to a lack of complete understanding of Alzheimer’s disease etiology. Neuronal activity disruptions have been described as contributing factors to the disease etiology and its progression. Anomalies in slow wave activity, specifically slow oscillations (oscillations <1Hz) important for consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients and might have contributed to their dementia. The cellular mechanisms of such disruptions however are unclear. Contributions of neuronal hyperactivity have been suggested. It is unknown whether macroglia contribute to hyperactivity and slow wave aberrations. Thus, there is an urgent need to understand the impact of macroglia on neuronal activity disruptions, such as slow waves, to better understand AD etiology and to alleviate its dementia burden. We will use transgenic mouse models of Alzheimer’s disease to systematically assess whether macroglia contributes to neuronal activity disruptions using calcium imaging with multiphoton microscopy. We will also investigate whether macroglia play a causal role in disruption of slow wave activity using optogenetics. We hypothesize that macroglia play a role greater than that of a homeostatic regulator of neuronal activity. We propose to employ optogenetics to control neuronal circuits aimed to restore neuronal activity and slow Alzheimer’s disease progression. Thus, our findings will determine the cellular and molecular relationships between neuronal activity and AD, with the targeting of macroglia as a novel therapeutic approach.