Molecular basis of age-related synaptic alterations

年龄相关突触改变的分子基础

• 批准号: 7683976
• 负责人: Gregorio Valdez
• 金额: $ 5.34万
• 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/7683976
• 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（由申请方提供）：精神功能中的神经元相关变化与中枢和外周神经系统中的形态学和分子学改变相关，并可能是由于中枢和外周神经系统中的形态学和分子学改变所致。大多数神经生物学家都认为，这些变化中有一些涉及突触，但对衰老与突触改变的关系知之甚少。神经肌肉接头（NMJ）是研究年龄相关的突触结构和功能变化以及阐明其分子基础的理想系统。令人兴奋的初步结果表明，老化导致NMJ的突触前和突触后成分的主要形态和分子变化。 在突触前，有较少的轴突，更多的静脉曲张的轴突和更多的轴突发芽。突触后部位通常是破碎的，部分受神经支配。伴随着这些形态学变化，三种突触粘附分子，层粘连蛋白α 4，层粘连蛋白β 2和聚集蛋白，在老年NMJ中显著减少。支持层粘连蛋白α 4在衰老中的作用，其缺失导致小鼠突触过早老化。令人惊讶的是，老年和层粘连蛋白α 4的缺乏并没有改变眼外NMJ的形态，这种肌肉也在神经肌肉疾病肌萎缩性侧索硬化症（ALS）中幸免。这些新的发现表明，层粘连蛋白α 4，层粘连蛋白aeta 2，聚集蛋白及其同源受体可能在突触老化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老化突触中的作用，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。我还将寻找与年龄相关的受体变化，如MuSK，整合素和P/Q型钙通道。为了测试层粘连蛋白β 2和聚集蛋白在衰老中的因果作用，我将使用条件和杂合子小鼠来评估它们的缺失或大量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弱甚至逆转年龄引起的对突触的有害影响的分子。因此，这些实验可以提供工具，以改善一些突触缺陷的认知和spinalmuscle疾病。