Aging and Alzheimer's Disease Potential Link with IGF1-R

描述（由申请人提供）：衰老是迟发性阿尔茨海默病（AD）的最重要的单一风险因素，占所有AD痴呆病例的约97%。我们最近发现，大脑的正常衰老的特征在于从TrkA到p75 NTR受体系统的渐进性转换，这导致第二信使神经酰胺的激活和淀粉样蛋白2-肽（A2）的产生增加。这些作用可以通过p75 NTR的遗传破坏和中性鞘磷脂酶（nSMase）（激活神经酰胺的酶）的生化抑制来阻断。在初步研究部分中，我们表明IGF 1-R信号传导的激活上调p75 NTR，同时下调TrkA。IGF 1-R下游的信号级联需要IRS 2、PI 3 K、PIP 3、Egr-1、HIPK 2，并且在PTEN和p44的抑制控制下。我们还发现IGF 1-R在A2生成的调控中作用于p75 NTR/TrkA的上游。此外，在p44+/+转基因小鼠中IGF 1-R信号的过度激活导致衰老的加速形式、早期TrkA到p75 NTR的转换以及A2的产生增加。最后，p44+/+，APP 695/swe双转基因小鼠发展出早期和严重形式的神经变性，导致在生命的第3个月死亡。上述事件均与神经酰胺的过度产生和BACE 1的分子稳定有关。因此，我们的研究揭示了衰老和AD之间的新分子联系，并将该领域引向新的方向，如果成功，将对预防一种预计到2050年将影响约1500万美国人的疾病产生直接影响。本申请的长期目标是分析IGF 1-R信号在AD发病机制中的作用，并评估其是否可以作为预防迟发性AD的新靶点。具体目标1将分析作用于IGF 1-R下游的信号分子的作用。我们已经描述了几个生化和遗传学的研究，在原代神经元和神经元细胞系。生物化学方法包括体外测定和药理学抑制剂，而遗传方法包括siRNA、反义寡核苷酸和靶向信号分子的显性突变体。我们还将使用器官型脑培养物和衰老动物模型，包括正常喂养（正常衰老）和热量限制（延迟衰老）的野生型小鼠，以及p44+/+小鼠（加速衰老）。具体目标2将在我们新开发的p44+/+，APP 695/swe小鼠模型中分析IGF 1-R信号传导对AD病理学的作用。为此，我们描述了生物化学，组织学和认知的方法。此外，我们还将用manumycin A（抑制神经酰胺的产生）治疗p44+/+、APP 695/swe小鼠，以评估我们是否可以阻断/延迟病理。最后，目标1（我们计划确定生化靶点）和目标2（我们计划描述第一个受过度活跃衰老计划控制的AD小鼠模型）之间的协调将使我们能够测试新的药理学策略，以预防与衰老相关的AD风险。公共卫生相关性：衰老是阿尔茨海默病（AD）的最重要的危险因素，AD是世界上痴呆症最常见的原因。由于我们正在经历的预期寿命的增加，预计到2050年，AD将影响全球4500万人。在过去的三年中，我们已经确定了一种新的分子途径，将衰老与AD神经病理学联系起来。我们还开发了第一个允许研究衰老对AD影响的小鼠模型。鉴于这些事件在AD发病机制中的作用，我们的研究结果对该疾病的神经生物学以及预防与衰老相关的AD风险具有深远的意义。这项提案的长期目标是扩大我们的发现，并充分表征我们已经确定的分子途径。这将使我们能够设计新的预防AD的药理学方法。

DESCRIPTION (provided by applicant): Aging is the single most important risk factor for late-onset Alzheimer's disease (AD), which represents ~97% of all cases of AD dementia. We have recently shown that normal aging of the brain is characterized by a progressive switch from the TrkA to the p75NTR receptor system that leads to activation of the second messenger ceramide and increased production of amyloid 2-peptide (A2). These effects can be blocked by genetic disruption of p75NTR and biochemical inhibition of neutral sphingomyelinase (nSMase), the enzyme that activates ceramide. In the Preliminary Studies section we show that activation of IGF1-R signaling up- regulates p75NTR while down-regulating TrkA. The signaling cascade downstream of IGF1-R requires IRS2, PI3K, PIP3, Egr-1, HIPK2, and is under the inhibitory control of PTEN and p44. We also show that IGF1-R acts up-stream of p75NTR/TrkA in the regulation of A2 generation. In addition, hyperactivation of IGF1-R signaling in p44+/+ transgenic mice leads to an accelerated form of aging, early TrkA to p75NTR switch, and increased production of A2. Finally, p44+/+, APP695/swe double-transgenic mice develop an early and severe form of neurodegeneration that results in death by the 3rd month of life. The above events were all linked to overproduction of ceramide and molecular stabilization of BACE1. Therefore, our studies have uncovered a novel molecular link between aging and AD, and are leading the field toward new directions that, if successful, will have direct impact on the prevention of a disease that is projected to affect ~15 million Americans by the year 2050. The long-term objective of this application is to analyze the role of IGF1-R signaling in the pathogenesis of AD and to assess whether it can serve as a novel target for the prevention of late-onset AD. Specific Aim 1 will analyze the role of the signaling molecules that act down-stream of IGF1-R. We have described several biochemical and genetic studies in both primary neurons and neuronal cell lines. The biochemical approach includes in vitro-assays and pharmacologic inhibitors, whereas the genetic approach includes siRNA, antisense oligonucleotides, and dominant mutants of the targeted signaling molecules. We will also use organotypic brain cultures and animal models of aging, including normally-fed (normal aging) and caloric-restricted (delayed aging) wild-type mice, and p44+/+ mice (accelerated aging). Specific Aim 2 will analyze the role of IGF1-R signaling on AD pathology in a our newly developed p44+/+, APP695/swe mouse model. For this purpose, we have described biochemical, histological, and cognitive approaches. In addition, we will also treat p44+/+, APP695/swe mice with manumycin A (which inhibits the production of ceramide) to assess whether we can block/delay the pathology. Finally, the coordination between Aim 1, where we plan to identify biochemical targets, and Aim 2, where we plan to characterize the first AD mouse model that is under the control of a hyperactive aging program, will allow us to test novel pharmacological strategies to prevent the AD-risk associated with aging. PUBLIC HEALTH RELEVANCE: Aging is the single most important risk factor for Alzheimer's disease (AD), which represents the most common cause of dementia in the World. Because of the increase in life expectancy that we are experiencing, AD is predicted to affect 45 million individuals worldwide by the year 2050. During the last three years we have identified a novel molecular pathway that links aging to AD neuropathology. We have also developed the first mouse model that allows to study the effect of aging on AD. Given the role that these events play in the pathogenesis of AD, our results have profound implications for the neurobiology of the disease and for the prevention of the AD-risk associated with aging. The long-term objective of this proposal is to expand upon our findings and fully characterize the molecular pathway that we have identified. This will allow us to design new pharmacologic approaches for the prevention of AD.