Neuromelanin Formation and Toxicity in the Locus Coeruleus: The Role of Norepinephrine Metabolism

About This Grant

PROJECT SUMMARY: Alzheimer’s Disease (AD) is the most common form of dementia worldwide, affecting one in nine people over the age of 65, with the incidence of this debilitating disease projected to increase. Recent evidence suggests that the locus coeruleus (LC) is the first brain region to show tau pathology in AD and undergoes catastrophic degeneration later in the disease. The LC is the brain’s primary source of norepinephrine (NE), a neurotransmitter critical for mood, arousal, stress responses, and cognition. Early dysfunction of the LC is thought to contribute to prodromal AD symptoms such as sleep disturbances and anxiety, while LC-NE neuron loss exacerbates cognitive decline. These findings make the LC a focal point for early detection and progression in AD, but the reasons for its selective vulnerability are unknown. The premise of this proposal is that neuromelanin (NM), a pigment-like substance that accumulates in the LC over a person’s life, contributes to its vulnerability in AD. NM, comprised of catecholamines and their metabolites, melanin pigments, heavy metals, oxidated lipids, and protein aggregates, is thought to initially serve a protective role in the brain by sequestering these toxic species. However, overaccumulation of NM may interfere with cellular machinery and contribute to pathology and degeneration. While most knowledge about the LC comes from rodents, mice and rats do not produce NM naturally, making it difficult to study of NM’s role in neurodegeneration. We and others have reported that ectopic expression of human tyrosinase (hTyr), the enzyme responsible for peripheral melanin production, can drive NM accumulation in the mouse LC, resulting in dysfunction and degeneration. Since catecholamine metabolism, linked to LC activity, is essential for NM formation, changes in neuronal firing rate and NE metabolites may contribute to NM over-accumulation, resulting in neuronal inflammation and cell death. In this proposed project, I will use viral-mediated hTyr expression to induce NM formation in the LC, and test how manipulations in cell activity and NE metabolism impact tau, NM accumulation, neuroinflammation, and cell death. In Aim 1 I will use DREADDs to control LC activity, measure firing rate via electrophysiology, and predict that increasing firing will exacerbate, while decreasing LC activity will ameliorate NM accumulation and toxicity. In Aim 2 I will genetically manipulate monoamine-oxidase-A (MAO-A), the primary metabolizing enzyme of LC NE, to determine if genetic variations in MAO-A activity can impact NM accumulation in the LC. I hypothesize that decreasing LC firing and NE metabolism will ameliorate NM accumulation, neuronal inflammation, and cell death in the LC, while increasing these functions will have deleterious consequences. Completing these aims will determine the functional consequences of NM accumulation at the earliest site of degeneration in AD, facilitating the development of therapeutics.