Mechanisms of disease and treatment in novel metabolic developmental brain disorders

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PROJECT SUMMARY The locus coeruleus (LC) is a vulnerable brain area implicated in neurodegenerative diseases such as AD/ADRD. LC has been documented as among the earliest brain regions to degenerate in AD/ADRD, and LC degeneration is correlated with disease pathogenesis in AD/ADRD. In our work from the Parent Award (R01NS121618), we show that the Gpt2-null mouse demonstrates the earliest known loss of LC neurons, by postnatal day 18, in any genetic mouse model yet studied. Prior studies have also demonstrated that LC degeneration occurs in several mouse models of AD/ADRD, although this degeneration occurs later in the life of the animal, such as at 6 months of age. The underlying mechanisms of LC neuronal vulnerability in AD/ADRD are unknown; therefore, there is a critical opportunity for progress through the investigation of Gpt2- mediated mechanisms in LC vulnerability in AD/ADRD. The overriding objectives of this Supplement Application, which are strongly in line with the Parent Award, are: 1) to begin to define Gpt2-mediated mitochondrial mechanisms of LC vulnerability; and 2) to determine the extent to which these Gpt2-mediated mechanisms underlie LC vulnerability in AD/ADRD genetic models. Elucidation of Gpt2-mediated mechanisms in LC neuron death, and in AD/ADRD, will serve as a foundation for novel paths to treatment in AD/ADRD, including potentially metabolite supplements being tested in the Parent Application. The research in the Supplement Application will also permit the formation of a collaborative team to investigate mechanisms of LC vulnerability in AD/ADRD and the collection of preliminary data for follow-up AD/ADRD grant applications. The finding of prominent and early LC neurodegeneration in the Gpt2-null mouse represents an important opportunity to advance LC research relevant to AD/ADRD. In summary, this new line of AD/ADRD research will have a sustained impact on the AD/ADRD field as the research addresses the clinically relevant topic of LC neurodegeneration in AD/ADRD and promises to build a path to new metabolic treatments.