Proteostasis dysregulation and the development of Alzheimer's-like neurodegeneration and dementia in Down syndrome

唐氏综合症中蛋白质稳态失调以及阿尔茨海默病样神经变性和痴呆的发展

• 批准号: 10595310
• 负责人: DOMENICO PRATICO
• 金额: $ 52.33万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595310
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Animal Model; Autopsy; Behavior; Biochemical; Birth; Brain; Brain Pathology; Brain region; Catabolism; Cell Death; Cell physiology; Cells; Cessation of life; Chromosome 21; Chromosomes; Congenital Disorders; Data; Defect; Dementia; Deposition; Development; Down Syndrome; Event; FRAP1 gene; Functional disorder; Gene Proteins; Health; Human Chromosomes; Hyperactivity; Incidence; Individual; Knowledge; Link; Literature; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Organ; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Physiological; Play; Protein Biosynthesis; Protein Precursors; Proteins; Publishing; Research; Role; Secondary to; Senile Plaques; Signal Pathway; Signal Transduction; Synapses; Syndrome; System; Trisomy; Tuberous Sclerosis; United States; behavioral impairment; brain tissue; gene product; in vivo Model; mouse Ts65Dn; mouse model; neuron loss; neuropathology; novel; novel therapeutics; programs; protein degradation; proteostasis; secretase; tau Proteins; tau aggregation; therapeutic target; tool; trafficking; virtual

Down syndrome (DS) is a congenital condition resulting from partial or complete triplication of human chromosome 21. Virtually all the subjects with DS develop widespread neuropathology including amyloid- neuritic plaques, synaptic dysfunction and neurodegeneration, reminiscent of Alzheimer's disease. While the extra copy of amyloid- precursor protein (APP) on chromosome 21 is thought to play a major role in the development of this type of pathologic phenotype in DS, the underlying mechanisms responsible for these changes and their contribution to neurodegeneration are still elusive. Compelling evidence supports the hypothesis that physiological cellular proteostasis is of critical importance for neuronal health and that the mammalian target of rapamycin (mTOR) is a master regulator of this vital cellular function. However, while we know that the system is altered in DS we do not know whether it plays a functional role in the pathogenesis of DS and the onset of neuropathology. In our preliminary data we found that compared with healthy matched controls mTOR is hyperactive in selected brain regions of DS patients. Importantly, we observed that in the same subjects the dysfunction directly correlates with the pathology. Moreover, we show that mTOR is altered in the brain of a well- established mouse model of DS, the Ts65Dn mice, at an early stage of the phenotype, and associates with biochemical evidence of cell loss, suggesting a link between mTOR, neuropathology and neurodegeneration in DS subjects. Taking into consideration the scientific rigor of the previously published literature together with our recent findings we now propose a novel working hypothesis: alteration of mTOR signaling pathway is responsible for the onset of the neuropathologic DS phenotype and represents a novel and viable therapeutic target against it in DS subjects. In this proposal, we will assess the temporal relationship between dysregulation of mTOR in the brain of DS patients and the development of the neuropathology. We will then focus on investigating early events responsible for this dysregulation in the same DS subjects. Next, to prove its direct role in the pathogenesis of the syndrome, we will study the effect that modulation of mTOR activity and expression levels has on behavior impairments and neuropathology using in vivo models of DS. The results of our proposed studies will elucidate early changes and the functional consequences of altered proteostasis secondary to dysregulated mTOR in the development of the neuropathologic phenotype in individuals with DS. Importantly, our findings have the potential to identify new therapeutic opportunities for delaying its onset and /or halting its progression.

唐氏综合症（DS）是一种先天性状况 人类染色体21。几乎所有具有DS的受试者都会发展宽度神经病理学 包括淀粉样蛋白 - 神经质斑块，突触功能障碍和神经变性，提醒您 阿尔茨海默氏病。而染色体上淀粉样蛋白前体蛋白（APP）的额外副本 21被认为在DS中这种病理表型的发展中起主要作用， 负责这些变化的基本机制及其对 神经变性仍然是弹性的。令人信服的证据支持以下假设 生理细胞蛋白抑制对于神经元健康至关重要，并且 雷帕霉素（MTOR）的哺乳动物靶标是该重要细胞功能的主要调节剂。 但是，尽管我们知道该系统在DS中发生了变化，但我们不知道它是否播放 在DS发病机理和神经病理学的发作中的功能作用。在我们的初步数据中 我们发现，与健康匹配的对照组相比，MTOR在选定的大脑中是多动的 DS患者的区域。重要的是，我们观察到，在同一受试者中，功能障碍直接 与病理相关。此外，我们表明MTOR在良好的大脑中发生了变化 在表型的早期阶段，已建立的DS的小鼠模型，TS65DN小鼠， 与细胞损失的生化证据相关联，表明MTOR之间有联系 DS受试者的神经病理学和神经退行性。考虑到科学 先前出版的文献的严谨以及我们最近的发现，我们现在提出了 新型工作假设：MTOR信号通路的改变是导致的 神经病理学DS表型，代表了一个新颖且可行的治疗靶标 它在DS主题中。在此提案中，我们将评估失调失调之间的临时关系 DS患者大脑中的MTOR和神经病理学的发展。然后我们会 专注于调查导致同一DS受试者中这种失调的早期事件。 接下来，为了证明其在综合征发病机理中的直接作用，我们将研究以下效果。 MTOR活性和表达水平的调节对行为障碍和 神经病理使用DS的体内模型。我们提出的研究的结果将阐明 早期变化和继发于失调的蛋白质造成病改变的功能后果 MTOR在DS个体中神经病理表型的发展中。重要的是， 我们的发现有可能确定推迟发作和的新治疗机会 /或停止其进展。