Nutrient-Induced Mitochondrial Activity (NiMA): A Novel Lysosome to Mitochondria Signaling Pathway, its mechanisms and role in Alzheimer's Disease

阿尔茨海默病(AD)是一种与衰老相关的神经退行性疾病，在美国约有580万人受到影响 美国。尽管近几十年来进行了密集的研究工作，但无论是有效的姑息治疗还是 治愈方法是可用的，很大程度上是因为我们对被破坏的分子机制的了解有限。 这种毁灭性的疾病。目前的研究表明，阿尔茨海默病的认知能力逐渐下降是通过 大脑中可溶性淀粉样β蛋白(Aβ)寡聚体(AβOs)和细胞内tau的同时有害作用。 然而，新的证据表明，阿尔茨海默病的发展也可能归因于进行性 脑细胞线粒体功能的恶化，尤其是神经元。此外，AD的开发已经 最近被认为与大脑对胰岛素-a等激素反应能力的进行性损害有关 这种情况被称为大脑胰岛素抵抗。来研究这些新兴但仍然难以捉摸的分子 AD的机制，我们问这个问题：AβOs的积累，tau， 阿尔茨海默病患者的线粒体能量代谢受损，胰岛素抵抗增加，如果是这样的话，是如何造成的？ 已知A-β-OS与神经元质膜相互作用，从而可能中断通讯 神经元与其环境之间的联系，并扰乱其正常功能。我们特别感兴趣的是如何 AβOS扰乱神经元对胰岛素或营养物质的正确反应能力及其影响 ATP的产生和其他线粒体的功能。沿着这个方向，我们最近发现了营养诱导 线粒体活性(NIMA)是溶酶体和线粒体之间的一条新的通讯途径，它 是由溶酶体相关的雷帕霉素复合体1的机械靶点(MTORC1)介导的。有趣的是， AD细胞模型中A-β-Os的异常积聚以tau依赖的方式干扰NIMA。在这 项目中，我们的目标是阐明介导NIMA的分子机制，并了解这一途径是如何 在AD中被AβOs和tau干扰，通过在培养的人神经元中筛选这一途径的调节因子并使用 双光子荧光寿命成像显微镜和最新的线粒体和代谢成像 在活体内的小鼠大脑。该项目的成功完成不仅将促进我们对这些问题的理解 最早的步骤发生在AD的进展中，但也可能导致新的治疗策略，这可能有助于我们 治愈这一疾病。

Alzheimer’s disease (AD) is an aging-related neurodegenerative disorder that affects ~5.8 million people in the United States. Despite intensive research efforts in recent decades, neither an effective palliative treatment nor a cure is available, largely due to our limited understanding of the molecular mechanisms that are disrupted in this devastating disease. Current research suggests that the gradual cognitive decline in AD occurs by the concurrent deleterious action of soluble amyloid-beta (Aβ) oligomers (AβOs) and intracellular tau in the brain. Emerging evidence, however, suggests that development of AD may also be attributed to a progressive deterioration of mitochondrial functioning in brain cells, especially neurons. Besides, AD development has recently been linked to a progressive impairment in brain’s ability to respond to hormones such as insulin—a condition known as brain insulin resistance. To investigate these emerging but still elusive molecular mechanisms of AD, we ask the question: is there any connection between AβOs accumulation, tau, compromised mitochondrial energy metabolism, and increased insulin resistance in the AD brain and if so, how? It is known that AβOs interact with the neuronal plasma membrane, which may interrupt communications between neurons and their environment and disrupt their normal functions. We are particularly interested in how the AβOs disrupts neuron’s ability to properly respond to the presence of insulin or nutrients and how it affects ATP production and other mitochondrial functions. Along this direction, we recently discovered Nutrient-Induced Mitochondrial Activity (NiMA), a novel communication pathway between the lysosome and mitochondria, which is mediated by the lysosome-associated mechanistic target of rapamycin complex 1 (mTORC1). Interestingly, the abnormal accumulation of AβOs in AD cellular models disrupted NiMA in a tau-dependent manner. In this project, we aim to elucidate molecular mechanisms mediating NiMA and to understand how this pathway is disrupted by AβOs and tau in AD, by screening regulator of this pathway in human neurons in culture and using two-photon fluorescence lifetime imaging microscopy and state-of-the-art mitochondrial and metabolic imaging of the mouse brain in vivo. Successful completion of this project not only will advance our understanding of these earliest steps occurred in AD progression, but also may lead to new therapeutic strategies that could help us cure this disease.