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（由申请人提供）：与年龄相关的心理功能变化与中央和周围神经系统中形态学和分子的改变有关，并且可能是由于中心神经系统的形态和分子改变。大多数神经生物学家都同意，其中一些变化涉及突触，但是衰老与突触改变的关系知之甚少。神经肌肉连接（NMJ）是检查突触中与年龄相关的结构和功能改变并阐明其分子碱基的理想系统。令人兴奋的初步结果表明，衰老会导致NMJ前后突触后成分的主要形态和分子变化。 从前气前，轴突较少，静脉曲张更多和轴突发芽更多。突触后部位通常被碎裂并部分支配。与这些形态学变化相关，三个突触粘附分子，层粘连蛋白α4，层粘连蛋白β2和Agrin在老年NMJ中显着降低。支持层粘连蛋白α4在衰老中的作用，其缺失会导致小鼠的早熟衰老。令人惊讶的是，老年和缺乏层粘连蛋白α4不会改变眼外NMJ的形态，肌肉也幸免于神经肌肉疾病，肌萎缩性外侧硬化症（ALS）。这些新颖的发现表明，层粘连蛋白α4，层粘连蛋白AETA2，Agrin及其同源受体可能在突触衰老和神经系统疾病中起关键作用。为了开始揭示这些分子在衰老突触中的作用，我将首先评估这些分子何时以及如何使用免疫组织化学和原位杂交减少。我还将在其受体中寻求与年龄相关的交替，例如麝香，整联蛋白和P/Q-Type钙通道。为了测试层粘连蛋白β2和Agrin在衰老中的因果作用，我将使用条件和杂合小鼠评估年轻成人NMJ的缺乏或大量减少导致缺陷。最后，为了探测衰老与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鉴定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，这些实验可以提供改善认知和脊髓肌疾病的许多突触缺陷的工具。