Kinases Linking Abeta and Tau to Synaptic Dysfunction

连接 Abeta 和 Tau 与突触功能障碍的激酶

• 批准号: 8611974
• 负责人: Lennart Mucke
• 金额: $ 45.78万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611974
• 关键词: AMPA Receptors; Abbreviations; Accounting; Address; Affect; Affinity; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Arachidonic Acids; Axonal Transport; Behavioral; Binding; Biological Neural Networks; Brain; Butyric Acids; Calcium; Calmodulin; Cathepsins B; Cognitive; Cognitive deficits; Cyan Fluorescent Protein; Data; Dendritic Spines; Dependovirus; Disease; Doxycycline; Electroencephalogram; Electroencephalography; EphB2 Receptor; Etiology; Fibronectins; Fluorescence; Frontotemporal Lobar Degenerations; Functional disorder; Funding; Genes; Grant; Green Fluorescent Proteins; Human; Impaired cognition; Impairment; In Vitro; Intervention; Knock-out; Light; Link; Long-Term Depression; Long-Term Potentiation; Mediating; Mediator of activation protein; Microtubule-Associated Proteins; Microtubules; Mitochondria; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neuraxis; Neurologic; Neuronal Dysfunction; Neurons; Phosphorylation; Phosphotransferases; Population; Progress Reports; Protein Tyrosine Kinase; Proteins; Reproducibility; Resistance; Synapses; Synaptic plasticity; Tauopathies; Testing; Tetracycline Control; Therapeutic; Trans-Activators; Transgenic Organisms; Western Blotting; behavioral impairment; density; dentate gyrus; enhanced green fluorescent protein; gamma-Aminobutyric Acid; granule cell; neuronal excitability; novel strategies; peptide A; postsynaptic; presynaptic; prevent; protective effect; protein distribution; public health relevance; research study; small hairpin RNA; synaptic function; tau Proteins; tau interaction; tau mutation

DESCRIPTION (provided by applicant): While Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are distinct diseases; we suspect that they share certain pathogenic mechanisms, particularly abnormalities in the intracellular distribution of cargoes that regulate synaptic activity. In some forms of FTLD, these abnormalities may result from specific mutations in the microtubule-associated protein tau that imparts gains of adverse function. In AD, they may result from indirect pathogenic interactions between wildtype tau and amyloid-¿ (A¿) peptides, which are widely thought to cause AD. This etiologic difference may account, at least in part, for the fact that these conditions affect different neuronal populations. Identifying common molecular mechanisms in AD and FTLD might help preserve both of these neuronal populations. We hypothesize that impairments of axonal transport by A¿ and wildtype tau in AD and by mutant tau in FTLD require interactions of tau with the tyrosine kinase Fyn. We further hypothesize that A¿ and tau cause abnormal distribution of NMDA receptors (NMDARs) in dendritic spines, at least in part, by increasing the Fyn/ephB2 tyrosine kinase ratio in the postsynaptic density. These pre- and postsynaptic mechanisms are not mutually exclusive. They might result from Fyn-mediated effects on tau, tau-mediated effects on Fyn, or both, and could contribute to A¿- and tau-dependent neurological deficits in dementing disorders. To assess these possibilities, we propose to Aim 1. determine whether interactions between tau and Fyn are required for A¿ and tau to impair synaptic and behavioral functions; Aim 2. determine whether interactions between tau and Fyn are required for A¿ and tau to impair axonal transport and to reduce the ratio of intrasynaptic to extrasynaptic NMDARs; and Aim 3. determine whether ephB2 protects against A¿-induced neuronal dysfunction by increasing the ratio of intrasynaptic to extrasynaptic NMDARs and whether ephB2's protective capacity depends on kinase activity. We hypothesize that human A¿ oligomers and FTLD-mutant tau will no longer impair synaptic and behavioral functions when interactions (binding or phosphorylation) between Fyn and tau are blocked (Aim 1). We further hypothesize that this protective effect involves at least two mechanisms: improvements in the axonal transport of synaptic activity-related proteins (Aim 2a) and increases in the ratio of intrasynaptic to extrasynaptic NMDARs (Aim 2b). We suspect that the latter mechanism also accounts for the ability of ephB2 to protect against A¿-induced neuronal dysfunction (Aim 3). The proposed experiments will test a number of mechanistic hypotheses that have not yet been tested conclusively and address questions to which there currently are no firm answers. The answers we expect to obtain will shed light on the mechanisms that cause neurological decline in AD and FTLD and could help identify novel strategies to prevent and reverse these devastating diseases.

描述（由申请人提供）：虽然阿尔茨海默病（AD）和额颞叶变性（FTLD）是不同的疾病；但我们怀疑它们具有某些共同的致病机制，特别是在某些形式的调节突触活动的细胞内分布异常。 FTLD，这些异常可能是由微管相关蛋白 tau 的特定突变引起的，这种突变会赋予 AD 不良功能，而在 AD 中，它们可能是由野生型之间的间接致病相互作用引起的。 tau 蛋白和淀粉样蛋白-¿ (A¿) 肽，被广泛认为是导致 AD 的原因，这种差异至少可以部分解释这些情况影响 AD 和 FTLD 的共同分子机制可能有助于保留这两种情况。我们勇敢地面对 A¿ 的轴突运输损伤。 AD 中的野生型 tau 和 FTLD 中的突变型 tau 需要 tau 与酪氨酸激酶 Fyn 相互作用。 tau 和 tau 至少部分通过增加突触后密度中的 Fyn/ephB2 酪氨酸激酶比例来导致树突棘中 NMDA 受体 (NMDAR) 的异常分布。这些突触前和突触后机制可能不是相互排斥的。 -对 tau 介导的影响，tau 介导的对 Fyn 的影响，或两者兼而有之，并且可能有助于 A¿ - 和 tau- 痴呆症中的神经依赖性缺陷 为了评估这些可能性，我们建议目标 1. 确定 A¿ 是否需要 tau 和 Fyn 之间的相互作用。和 tau 损害突触和行为功能；目标 2. 确定 A¿ 是否需要 tau 和 Fyn 之间的相互作用和 tau 损害轴突运输并降低突触内与突触外 NMDAR 的比率；以及目标 3. 确定 ephB2 是否可以预防 A¿ -通过增加突触内与突触外 NMDAR 的比例诱导神经元功能障碍，以及 ephB2 的保护能力是否依赖于激酶活性。当 Fyn 和 tau 之间的相互作用（结合或磷酸化）被阻断时，寡聚体和 FTLD 突变 tau 将不再损害突触和行为功能（目标 1），我们进一步发现这种保护作用至少涉及两种机制：轴突运输的改善。突触活动相关蛋白（目标 2a）的增加以及突触内与突触外 NMDAR 的比例增加（目标 2b）。后一种机制也解释了 ephB2 抵御 A¿引起的神经元功能障碍（目标 3）。拟议的实验将检验一些尚未得到最终检验的机制假设，并解决目前尚无确定答案的问题。我们期望获得的答案将揭示该机制。导致 AD 和 FTLD 的神经功能衰退，有助于确定预防和逆转这些毁灭性疾病的新策略。