NEUROLOGICAL DEFICITS DUE TO TOXIC A BETA OLIGOMERS

描述(摘自申请人摘要)：本申请涉及一项新的 Abeta在AD中作用的可能性。它被指定调查 非纤维性神经细胞引起的突触可塑性丧失和神经细胞死亡 阿贝塔齐聚物。低聚物在AD大脑中积累，目前最好的证据 表明它们促进了疾病的发展，潜在地解释了 与淀粉样蛋白的相关性不完全。目标集中在以下三个关键属性上 低聚物(称为“ADDL”，用于Abeta衍生的可扩散配体)。(I) ADDLS在不到一小时的时间内抑制LTP，这是已知对 Abeta的形式。(Ii)ADDL通过一种被阻断的机制杀死海马神经元 NMDA受体偶联蛋白酪氨酸激酶Fyn的胚系敲除 和破伤风诱导的LTP。(Iii)ADDLS与下列细胞表面蛋白结合 对胰酶敏感，并聚集在点状“热点”。我们的目标是 了解ADSL神经毒性的分子基础。将有两个假设 已评估。首先，ADDLS可能是通过以下途径造成损害的小蛋白配体 干扰Fyn信号转导，一种由特定毒素介导的结果 感受器。或者，ADDL可能会在很少或没有的情况下破坏细胞的完整性 特异性，产生细胞生理的全球分解，包括 LTP的丢失，最终导致细胞死亡。对这些假说的预测将 要接受提案目标的检验。 目的1.LTP或神经传递-ADDLS对突触的影响 LTP，或突触功能广泛受损。 目的2.可塑性的类型--ADDLS影响多种类型的神经元 可塑性，还是只有破伤风引起的LTP？ 目的3.分子影响--毒性是否源于ADDLS对FYN的影响，或者确实 ADDLS攻击在其他甚至多个站点？ 目的4.细胞表面反应--ADDL与特定的“毒素受体”结合，或 额外的活性不依赖于唯一的结合位点吗？ 这一应用的结果将为理解 人脑中发现的Abeta寡聚体的作用。在最好的情况下， 这些发现将为治疗提供新的靶点，最终可能 逆转，而不仅仅是减缓AD内存损害。

DESCRIPTION (From the Applicant's Abstract): This application concerns a new possibility for the role of Abeta in AD. It is designated to investigate the loss of synaptic plasticity and death of nerve cells caused by nonfibrillar Abeta oligomers. Oligomers accumulate in AD brain, and current best evidence indicates they contribute to disease progression, potentially accounting for the imperfect correlation with amyloid. Aims focus on three key properties of oligomers (referred to as "ADDLs," for Abeta derived diffusable ligands). (i) ADDLs inhibits LTP in under an hour, one of the fastest known responses to any form of Abeta. (ii) ADDLs kill hippocampal neurons by a mechanism blocked by germline knockout of Fyn, a protein tyrosine kinase coupled to NMDA receptors and tetanus-induced LTP. (iii) ADDLs bind to cell surface proteins that are trypsin-sensitive and cluster at punctate "hot spots." The goal is to understand the molecular basis for ADDL neurotoxicity. Two hypotheses will be evaluated. First, ADDLs may be small protein ligands that cause damage by disturbing Fyn signal transduction, a consequence mediated by specific toxin receptors. Alternatively, ADDLs may disrupt cell integrity with little or no specificity, generating a global breakdown of cell physiology that includes loss of LTP and culminates in cell death. Predictions of these hypotheses will be tested by the proposal's AIMs. Aim 1. LTP or neurotransmission-Is the synaptic impact of ADDLs specific for LTP, or is synaptic function broadly impaired. Aim 2. Types of plasticity-Do ADDLs affect multiple types of neuronal plasticity, or only tetanus induced LTP? Aim 3. Molecular impact-Does toxicity stem form ADDLs impact on Fyn, or do ADDLs attack at alternative and perhaps multiple sites? Aim 4. Cell surface reactions-Are ADDLs bound by specific "toxin receptors," or is ADDL activity not dependent on unique binding sites? Results from this application will give a new basis for understanding the actions of Abeta oligomers found in human brain. In a best-case outcome, findings would provide novel targets for therapies that ultimately could reverse and not just slow down AD memory impairment.