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: 8330529
• 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/8330529
• 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.

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