Mechanisms of disease and treatment in novel metabolic developmental brain disorders

项目总结 蓝斑(LC)是一个脆弱的大脑区域，与神经退行性疾病有关，如 AD/ADRD。LC已被证明是AD/ADRD中最早退化的脑区之一，而LC 退行性疾病与AD/ADRD的发病机制密切相关。在我们的作品中来自家长奖 (R01NS121618)，我们发现Gpt2缺失的小鼠表现出已知的最早的LC神经元丢失，通过 出生后第18天，在任何尚未研究过的遗传小鼠模型中。先前的研究也表明，LC 在AD/ADRD的几种小鼠模型中会发生退化，尽管这种退化发生在生命的后期 动物的，如6个月大的。LC神经元易损性的潜在机制 AD/ADRD是未知的；因此，通过对Gpt2的调查有一个取得进展的关键机会-- AD/ADRD中LC漏洞的中介机制。本副刊的首要目标 与家长奖高度一致的应用程序是：1)开始定义Gpt2介导的 2)确定这些Gpt2介导的程度 机制是AD/ADRD遗传模型中LC漏洞的基础。Gpt2介导的机制的阐明 在LC神经元死亡和AD/ADRD中，将作为治疗AD/ADRD的新途径的基础， 包括在父申请中测试的潜在代谢物补充剂。《科学与技术》中的研究 补充申请还将允许成立一个合作小组来研究LC的机制 AD/ADRD中的脆弱性，以及为后续AD/ADRD赠款申请收集初步数据。这个 在Gpt2缺失小鼠中发现显著的早期LC神经变性是一个重要的 有机会推进与AD/ADRD相关的LC研究。总而言之，AD/ADRD研究的这一新路线 将对AD/ADRD领域产生持续影响，因为这项研究解决了LC的临床相关主题 AD/ADRD中的神经变性，并承诺建立一条通往新的代谢治疗的道路。

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.