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

项目总结 尽管长期以来人们一直关注淀粉样β蛋白(Aβ)斑块在阿尔茨海默病(AD)中的作用 病理上，下游过程连接因果关系尚不清楚，限制了靶向合成 治疗性化合物。此外，关于Aβ的哪些种类具有细胞毒性和临床应用也存在争议 旨在直接针对Aβ的试验没有预期的那么成功。这增加了对 需要退一步，定义替代的系统范围的变化，这些变化加剧了AD的病理，并可能 取而代之的是调节以降低疾病风险。代谢动态平衡的丧失是衰老的标志之一 这一过程可能与AD的病理生理和神经退行性变有关。为了支持这一假设， 最近的数据显示，除了II型糖尿病之外，伴有代谢功能障碍的肥胖患者的风险也增加了 而饮食限制(DR)维持代谢动态平衡，具有神经保护作用。加在一起， 这些数据表明，AD的一个关键潜在风险因素可能是代谢，这可能是治疗的靶点 功能障碍。然而，能量学年龄变化与阿尔茨海默病之间的因果联系尚不清楚。安培- 激活的蛋白激酶(AMPK)是一种高度保守的能量稳态的主要调节因子，我们和 其他人则表明，能量学与多种物种的衰老速度有关。AMPK是一种中枢动态平衡 多种细胞系统的调节者，包括转录和翻译后信号网络，蛋白质 动态平衡和细胞器动力学。以下哪一项将AMPK和代谢功能障碍的影响与 广告情况尚不清楚。由于负反馈环倾向于存在以使细胞返回到内稳态、针对多个 在AD中，AMPK的效应器可能比单独使用AMPK更有效。我们最近报道了 AMPK通过重塑系统线粒体代谢来延长线虫的寿命，这是 与周围组织中线粒体网络的碎裂有关。此外，我们还展示了 RNA剪接动态平衡中AMPK对长寿和UPRER调节剂XBP-1的影响。在这里我们使用 线虫加速发现调节AMPK对AD影响的细胞机制 病理生理学，并同时靶向多个网络以减少年龄和Aβ引起的脑功能下降 神经功能。

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.