Reversing Loss of Metabolic Homeostasis to Ameliorate Alzheimer's Disease Pathogenicity

逆转代谢稳态的丧失以改善阿尔茨海默病的致病性

• 批准号: 10388149
• 负责人: William B Mair
• 金额: $ 39.88万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388149
• 关键词: 5' -AMP-activated protein kinase; Acute; Age; Age of Onset; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Animals; Back; Biochemical Pathway; Biological; Caenorhabditis elegans; Calcium; Cell physiology; Cells; Cellular biology; Clinical Trials Design; Communication; Data; Defect; Disease susceptibility; Environment; Feedback; Functional disorder; Genetic; Genetic Transcription; Goals; Homeostasis; Intake; Learning; Link; Longevity; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mission; Mitochondria; Nerve Degeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Onset of illness; Organelles; Pathogenicity; Peptides; Peripheral; Phenformin; Process; Protein Kinase; Public Health; RNA; RNA Splicing; Regulation; Reporter; Reporting; Research; Reverse engineering; Role; Signal Transduction; Site; System; Tissues; United States National Institutes of Health; age effect; age related; aged; cell type; cytotoxic; dietary restriction; disorder risk; in vivo; metabolomics; mitochondrial metabolism; novel therapeutics; obese patients; prevent; proteostasis; targeted treatment

PROJECT SUMMARY Despite a long-term focus on the role of Amyloid Beta (Aβ) peptide plaques in Alzheimer’s Disease (AD) pathology, downstream processes connecting cause to effect remain unclear, limiting the synthesis of targeted therapeutic compounds. Furthermore, controversy surrounds which species of Aβ are cytotoxic, and clinical trials designed to target Aβ directly have been less successful than anticipated. This adds critical importance to the need to step back and define alternative systems-wide changes that exacerbate AD pathology and might instead be modulated to lower disease risk. Loss of metabolic homeostasis is one of the hallmarks of the aging process that might contribute to AD pathophysiology and neurodegeneration. In support of this hypothesis, recent data show that, beyond type II diabetes, obese patients with metabolic dysfunction have increased risk of AD, while dietary restriction (DR) maintains metabolic homeostasis and is neuroprotective. Taken together, these data suggest a key underlying risk factor for AD that might be targeted for therapeutics is metabolic dysfunction. However, causal links between age-onset changes in energetics and AD are unclear. AMP- activated protein kinase (AMPK) is a highly conserved master regulator of energy homeostasis that we and others have shown links energetics to the rate of aging in multiple species. AMPK is a central homeostatic regulator of multiple cellular systems including transcriptional and post-translational signaling networks, protein homeostasis, and organelle dynamics. Which of these links the effects of AMPK and metabolic dysfunction to AD is unclear. Since negative feedback loops tend to exist to return a cell to homeostasis, targeting multiple effectors of AMPK in tandem rather than AMPK alone may prove more effective in AD. We recently reported that AMPK increases lifespan in C. elegans via remodeling of systemic mitochondrial metabolism, which correlates with mitochondrial network fragmentation in peripheral tissues. In addition, we have shown a role for RNA splicing homeostasis in the effects of AMPK on longevity and the UPRER modulator XBP-1. Here we use C. elegans to expedite discovery of cellular mechanisms that modulate the effect of AMPK on AD pathophysiology, and target multiple networks simultaneously to reduce age and Aβ induced decline in neuronal function.

项目摘要 尽管长期关注淀粉样β（Aβ）肽斑块在阿尔茨海默病（AD）中的作用， 病理学，连接因果关系的下游过程仍然不清楚，限制了靶向药物的合成。 治疗化合物。此外，关于哪种Aβ具有细胞毒性和临床意义的争论还存在争议。 直接靶向Aβ的试验不如预期成功。这一点至关重要， 需要退后一步，定义加剧AD病理学的替代系统范围的变化， 而是通过调节来降低疾病风险。代谢平衡的丧失是衰老的标志之一 这可能有助于AD病理生理学和神经退行性变的过程。为了支持这一假设， 最近的数据显示，除了II型糖尿病，患有代谢功能障碍的肥胖患者 而饮食限制（DR）可维持代谢稳态并具有神经保护作用。综合起来看， 这些数据表明，可能成为治疗靶点的AD的一个关键潜在危险因素是代谢 功能障碍然而，年龄发作的能量变化和AD之间的因果关系尚不清楚。AMP- 活化蛋白激酶（AMPK）是一种高度保守的能量稳态主调节因子， 其他人已经证明了能量学与多个物种的衰老速度之间的联系。AMPK是一种中枢稳态蛋白， 多种细胞系统的调节剂，包括转录和翻译后信号网络，蛋白质 稳态和细胞器动力学。哪一项将AMPK和代谢功能障碍的作用与 AD不清楚。由于负反馈回路倾向于存在以使细胞恢复稳态，因此靶向多个 在AD中，AMPK串联效应物比AMPK单独效应物更有效。我们最近报道 AMPK能延长C. elegans通过重塑系统线粒体代谢， 与外周组织中的线粒体网络断裂相关。此外，我们还展示了 AMPK对寿命和UPRER调节剂XBP-1的影响中的RNA剪接稳态。这里我们使用 C. elegans加速发现调节AMPK对AD作用的细胞机制 同时靶向多个网络，以减少年龄和Aβ诱导的 神经元功能