Neuron-Targeted Caveolin-1 as a Therapy for Age-Related Neurodegeneration

描述(由申请人提供)： 认知功能减退正在成为老年人口中最严重的健康问题之一，85岁以上的成年人中约有一半患有阿尔茨海默病(AD)。随着人口老龄化，患有认知衰退的个人数量将会增加。年龄本身就会增加中风的风险，增加阿尔茨海默病和其他形式的痴呆症的患病率。学习、记忆和神经元的发育都依赖于突触。受体和相关蛋白聚集在一起塑造和塑造突触后密度，以实现高保真的信号转导，从而快速调节神经功能，这是一种随年龄变化的组织。已经提出了许多理论来解释这种老龄化的赤字。这些理论认为是遗传、生化或生理成分。尽管与年龄相关的神经变性和认知功能下降的机制尚不清楚，但它们可能涉及促进生存和促进生长的神经元信号蛋白和分子的组织异常，这些信号蛋白和分子是遗传、生化和生理缺陷的综合结果。有效神经元信号的关键是膜/脂筏(MLR)，即富含鞘脂、胆固醇和支架蛋白的质膜微域；它们起着组织膜信号和运输的作用。MLR有助于协调、精确和快速地调节细胞功能。MLR也集中在生长锥体内，对轴突的生长和引导是必不可少的，对突触的发育和稳定也是必不可少的。MLR的一个关键成分是小窝蛋白-1(Cav-1)，它是一种胆固醇结合蛋白，不仅组织和支架了包括NMDAR、AMPAR、GPCRs和TrkR在内的多种受体，而且还组织和支撑了Src和ERK1/2等信号分子和那些调节cAMP形成的分子。因此，MLR含有对神经元生存和生长至关重要的受体和信号分子。我们实验室的初步数据显示，中年(12m)和老龄(&gt；18m)小鼠海马区MLR、突触体及其相关蛋白(Cav-1、NMDAR、AMPAR、TrkR和PSD-95)和突触显著减少；年轻Cav-1 KO小鼠表现出早期衰老的神经病理。重要的是，Cav-1在神经元中过表达：1)增加MLR、NMDAR、AMPAR和TrkB；2)增强BDNF介导的TrkB、Akt和ERK1/2的磷酸化；3)增强NMDAR介导的P-Src、P-CaMKII和P-ERK1/2的激活；4)增加NMDAR、多巴胺1受体(D1R)、5-HT6和Forsklin介导的cAMP的形成；5)增加树突的萌发和分支。因此，Cav-1作为支持生存和促进生长的神经元信号通路的纽带。本质上，单一干预Cav-1在神经元中的过度表达导致大量信号通路的上调，这些信号通路显著促进内源性大脑修复和再生。因此，它可能提供一个控制点，可以在治疗上有针对性地恢复老年退伍军人的神经功能。

DESCRIPTION (provided by applicant): Cognitive decline is emerging as one of the greatest health problems in the elderly population, with approximately half of all adults over the age of 85 suffering from Alzheimer's disease (AD). The number of individuals afflicted with cognitive decline will increase as the population ages. Age alone increases the risk of stroke and the prevalence of AD and other forms of dementia. Learning, memory and the development of neurons are dependent upon synapses. Receptors and associated proteins aggregate to mold and shape postsynaptic densities in order to permit high fidelity signal transduction leading to rapid regulation of neuronal function, an organization which is altered with age. A number of theories have been proposed to account for this aging deficit. These theories suggest a genetic, a biochemical, or a physiologic component. Though the mechanisms that underlie age-related neurodegeneration and cognitive decline are not clear, they likely involve abnormalities in the organization of pro-survival and pro-growth neuronal signaling proteins and molecules that are a combined result of genetic, biochemical, and physiologic deficiencies. Key to efficient neuronal signaling are membrane/lipid rafts (MLR), plasmalemmal microdomains enriched in sphingolipids, cholesterol, and scaffolding proteins; they serve to organize membrane signaling and trafficking. MLR facilitate coordinated, precise and rapid regulation of cell function. MLR are also concentrated within growth cones and are essential for axonal growth and guidance and are essential for the development and stabilization of synapses. A key component of MLR is caveolin-1 (Cav-1), a cholesterol binding protein that organizes and scaffolds not only a multitude of receptors including NMDAR, AMPAR, GPCRs, and TrkR, but also signaling molecules such as Src and ERK1/2 and those that regulate cAMP formation. Hence, MLR contain the receptors and signaling molecules that are critical to neuronal survival and growth. Preliminary data from our laboratory demonstrate that middle aged (12 m) and aged mice (>18 m) exhibit significant decreases in MLR, reduced synaptosomes and their associated proteins (Cav-1, NMDAR, AMPAR, TrkR, and PSD-95) and synapses in the hippocampus; young Cav-1 KO mice exhibit early aging neuropathology. Importantly, Cav-1 overexpression in neurons: 1) increases MLR, NMDAR, AMPAR, and TrkB; 2) enhances BDNF-mediated phosphorylation of TrkB, Akt, and ERK1/2; 3) enhances NMDAR- mediated activation of P-Src, P-CaMKII, and P-ERK1/2; 4) increases NMDAR, Dopamine 1 receptor (D1R), 5-HT6, and forskolin-mediated cAMP formation; and 5) increases dendritic sprouting and branching. Thus, Cav-1 serves as a nexus for pro-survival and pro-growth neuronal signaling. In essence, the single intervention of Cav-1 overexpression in neurons leads to the upregulation of a multitude of signaling pathways that significantly enhance endogenous brain repair and regeneration. As such, it may provide a control point that can be therapeutically targeted to restore neuronal function in the aging Veteran population.