Molecular basis of age-related synaptic alterations

年龄相关突触改变的分子基础

• 批准号: 7892421
• 负责人: Gregorio Valdez
• 金额: $ 5.39万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2011-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892421
• 关键词: Affect; Age; Aging; Aging-Related Process; Agrin; Amyotrophic Lateral Sclerosis; Area; Attenuated; Axon; Cell Adhesion Molecules; Cognitive; Defect; Development; Disease; Extracellular Matrix; Immunohistochemistry; In Situ Hybridization; Integrins; Knockout Mice; Laminin; Laminin Receptor; Lead; Maintenance; Messenger RNA; Molecular; Molecular Structure; Morphology; Mus; Muscle; Mutant Strains Mice; Nervous system structure; Neuromuscular Diseases; Neuromuscular Junction; Peripheral Nervous System; Play; Premature aging syndrome; Psyche structure; Q-Type Calcium Channels; Role; Site; Staging; Swelling; Synapses; System; Testing; age effect; age related; aged; axonal sprouting; base; laminin S; mouse model; mutant; nerve supply; nervous system disorder; normal aging; novel; orbit muscle; postsynaptic; premature; receptor; research study; tool; young adult

DESCRIPTION (provided by applicant): Age-related changes in mental function are associated with, and are presumably due to, morphological and molecular alterations in the central and peripheral nervous systems. Most neurobiologists agree that some of these changes involve synapses, but relationships of aging to synaptic alteration are poorly understood. The neuromuscular junction (NMJ) is an ideal system to examine age-associated structural and functional alterations in synapses, and to elucidate their molecular bases. Exciting preliminary results show that aging causes major morphological and molecular changes to the pre- and post-synaptic components of the NMJ. Presynaptically, there are fewer axons, more varicose axons and more axonal sprouting. The postsynaptic sites are often fragmented and partially innervated. Concomitant with these morphological changes, three synaptic adhesion molecules, laminin alpha4, laminin beta2 and agrin, are significantly decreased in aged NMJs. Supporting a role for laminin alpha4 in aging, its deletion causes premature synaptic aging in mice. Surprisingly, old age and the absence of laminin alpha4 do not alter the morphology of extraocular NMJs, a muscle also spared in the neuromuscular disease, amyotrophic lateral sclerosis (ALS). These novel findings suggest that laminin alpha4, laminin aeta2, agrin and their cognate receptors may play a critical role in synaptic aging and neurological disorders. To begin uncovering the role of these molecules in aging synapses, I will first assess when and how these molecules decrease using immunohistochemistry and in situ hybridization. I will also seek age-related alternations in their receptors, such as MuSK, Integrins and P/Q-type calcium channels. To test for a causal role for laminin beta2 and agrin in aging, I will use conditional and heterozygous mice to assess if their absence or substantial decrease causes defects in young adult NMJs. Finally, to probe the relationship of aging to ALS, I will assess the expression of synaptic adhesion molecules in a mouse model of ALS. Together, these studies may allow me to identify molecules that can attenuate or even reverse age-induced deleterious effects on synapses. Consequently, these experiments could provide tools to ameliorate a number of synaptic defects underlying cognitive and spinalmuscular diseases.

描述（由申请人提供）：与年龄相关的心理功能变化与中枢和周围神经系统的形态和分子变化有关，并且可能是由于中枢和周围神经系统的形态和分子变化引起的。大多数神经生物学家都认为其中一些变化涉及突触，但人们对衰老与突触改变的关系知之甚少。神经肌肉接头（NMJ）是检查突触中与年龄相关的结构和功能变化并阐明其分子基础的理想系统。令人兴奋的初步结果表明，衰老会导致 NMJ 突触前和突触后成分发生重大形态和分子变化。 突触前，轴突较少，曲张轴突较多，轴突出芽较多。突触后位点通常是支离破碎的并且部分受神经支配。伴随着这些形态变化，三种突触粘附分子，层粘连蛋白α4、层粘连蛋白β2和集聚蛋白，在衰老的NMJ中显着减少。层粘连蛋白α4在衰老过程中发挥着重要作用，其缺失会导致小鼠突触过早衰老。令人惊讶的是，年老和层粘连蛋白 α4 的缺失不会改变眼外 NMJ 的形态，这种肌肉在神经肌肉疾病肌萎缩侧索硬化症 (ALS) 中也能幸免。这些新发现表明层粘连蛋白α4、层粘连蛋白aeta2、集聚蛋白及其同源受体可能在突触衰老和神经系统疾病中发挥关键作用。为了开始揭示这些分子在衰老突触中的作用，我将首先使用免疫组织化学和原位杂交评估这些分子何时以及如何减少。我还将寻找其受体中与年龄相关的变化，例如 MuSK、整合素和 P/Q 型钙通道。为了测试层粘连蛋白 beta2 和 agrin 在衰老中的因果作用，我将使用条件小鼠和杂合小鼠来评估它们的缺失或大幅减少是否会导致年轻成年 NMJ 的缺陷。最后，为了探讨衰老与 ALS 的关系，我将评估 ALS 小鼠模型中突触粘附分子的表达。总之，这些研究可能使我能够识别出可以减轻甚至逆转年龄引起的对突触有害影响的分子。因此，这些实验可以提供改善认知和脊髓肌肉疾病的许多突触缺陷的工具。