Mapping the vulnerable locus coeruleus pathways in aging and AD

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Project Summary Alzheimer’s disease is a devastating dementia with no known cure. While research has advanced our knowledge of the genetics and molecular biology of AD, it is not yet known why some areas of the brain are affected, while others are spared. Additionally, the sensitivity of circuits and synaptic connections in disease progression are not known. We will examine the connectivity of the locus coeruleus (LC), which projects to most areas of the brain, and is one of the regions to show pathology earliest in AD. We will characterize the populations of these neurons based on their connectivity and sensitivity to degeneration with aging and in AD model mice, both from a global connectome level and with single-cell approaches for molecular signatures. Additionally, we with look in more detail at the entorhinal cortex, one of the recipients of LC connections with preferential cell loss, and characterize the specific populations and input/output relationships in response to aging and LC pathology.