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

神经元靶向 Caveolin-1 作为年龄相关神经退行性疾病的治疗方法

• 批准号: 8452592
• 负责人: BRIAN P HEAD
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452592
• 关键词: 5-HT6 receptor; Accounting; Adult; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Attenuated; Biochemical; Brain; Brain-Derived Neurotrophic Factor; Caveolins; Cell membrane; Cell physiology; Cells; Cholesterol; Cyclic AMP; Data; Dementia; Development; Dopamine; Elderly; Exhibits; Forskolin; Gap Junctions; Gene Expression Regulation; Genetic; Glutamate Receptor; Growth; Growth Cones; Health; Hippocampus (Brain); Impaired cognition; Individual; Intervention; Laboratories; Learning; Life; MAPK3 gene; Mediating; Membrane; Membrane Fluidity; Membrane Lipids; Membrane Microdomains; Memory; Molds; Morbidity - disease rate; Motor; Mus; Natural regeneration; Nerve Degeneration; Nerve Growth Factor Receptors; Neurodegenerative Disorders; Neurons; Pathway interactions; Phenotype; Phosphorylation; Physiological; Population; Post-Translational Protein Processing; Prevalence; Proteins; Receptor Signaling; Regulation; Research; Risk; Scaffolding Protein; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Sphingolipids; Staging; Stroke; Synapses; Synaptosomes; Testing; Up-Regulation; Veterans; Work; age related; age related neurodegeneration; aged; aging brain; axon growth; axonal guidance; axonal sprouting; brain repair; calmodulin-dependent protein kinase II; caveolin 1; cholesterol biosynthesis; cholesterol-binding protein; clinically relevant; cognitive function; density; extracellular; improved; middle age; neuron development; neuron loss; neuronal growth; neuronal survival; neuropathology; novel strategies; overexpression; postsynaptic; programs; protein aggregate; receptor; restoration; scaffold; theories; trafficking; uptake

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.

描述（由申请人提供）： 认知能力下降正在成为老年人群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，患有认知能力下降的人数将会增加。年龄本身就会增加中风的风险以及 AD 和其他形式的痴呆症的患病率。 神经元的学习、记忆和发育都依赖于突触。受体和相关蛋白质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，神经元功能随着年龄的增长而改变。人们提出了许多理论来解释这种老龄化缺陷。这些理论表明有遗传、生化或生理成分。尽管与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，这是遗传、生化和生理缺陷的综合结果。 有效神经元信号传导的关键是膜/脂筏 (MLR)、富含鞘脂、胆固醇和支架蛋白的质膜微结构域；它们负责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，对于轴突生长和引导至关重要，对于突触的发育和稳定也至关重要。 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.因此，MLR 包含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）的MLR显着降低，海马突触体及其相关蛋白（Cav-1、NMDAR、AMPAR、TrkR和PSD-95）和突触减少；年轻的 Cav-1 KO 小鼠表现出早期衰老的神经病理学。重要的是，Cav-1 在神经元中过度表达：1) 增加 MLR、NMDAR、AMPAR 和 TrkB； 2) 增强 BDNF 介导的 TrkB、Akt 和 ERK1/2 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 和毛喉素介导的 cAMP 形成； 5) 增加树突发芽和分枝。 因此，Cav-1 充当促生存和促生长神经元信号传导的纽带。本质上，对神经元中 Cav-1 过度表达的单一干预会导致多种信号通路的上调，从而显着增强内源性大脑修复和再生。因此，它可能提供一个控制点，可以在治疗上靶向恢复老龄退伍军人群体的神经元功能。