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

描述（由申请人提供）： 认知能力下降正在成为老年人最大的健康问题之一，85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，认知能力下降的人数将增加。年龄本身就增加了中风的风险以及AD和其他形式痴呆的患病率。 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以塑造和塑造突触后密度，以允许高保真信号转导，从而导致神经元功能的快速调节，神经元功能是随着年龄而改变的组织。人们提出了许多理论来解释这种老化缺陷。这些理论暗示了遗传、生物化学或生理成分。虽然年龄相关的神经退行性变和认知能力下降的机制尚不清楚，但它们可能涉及促生存和促生长神经元信号蛋白和分子的组织异常，这些蛋白和分子是遗传、生物化学和生理缺陷的综合结果。 有效的神经元信号传导的关键是膜/脂筏（MLR），质膜微区富含鞘脂，胆固醇和支架蛋白;它们用于组织膜信号传导和运输。MLR有助于协调、精确和快速地调节细胞功能。MLR也集中在生长锥内，并且对于轴突生长和引导是必需的，并且对于突触的发育和稳定是必需的。MLR的关键组分是小窝蛋白-1（Cav-1），其是一种胆固醇结合蛋白，不仅组织和支架众多受体，包括NMDAR、AMPAR、GPCR和TrkR，而且组织和支架信号分子，如Src和ERK 1/2以及调节cAMP形成的那些。因此，MLR含有对神经元存活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表明，中年（12 m）和老年小鼠（> 18 m）表现出MLR显著降低，海马中突触体及其相关蛋白（Cav-1、NMDAR、AMPAR、TrkR和PSD-95）和突触减少;年轻Cav-1 KO小鼠表现出早期衰老神经病理学。重要的是，Cav-1在神经元中的过表达：1）增加MLR、NMDAR、AMPAR和TrkB; 2）增强BDNF介导的TrkB、Akt和ERK 1/2的磷酸化; 3）增强NMDAR介导的P-Src、P-CaMKII和P-ERK 1/2的活化; 4）增加NMDAR、多巴胺1受体（D1R）、5-HT 6和毛喉素介导的cAMP形成;和5）增加树突发芽和分枝。 因此，Cav-1作为促存活和促生长神经元信号传导的纽带。本质上，神经元中Cav-1过表达的单一干预导致大量信号传导途径的上调，这些信号传导途径显著增强内源性脑修复和再生。因此，它可以提供一个控制点，可以在治疗上靶向恢复老年退伍军人群体的神经元功能。

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.