NEUROLOGICAL DEFICITS DUE TO TOXIC A BETA OLIGOMERS

描述（来自申请人的摘要）：本申请涉及一种新的 Abeta在AD中的作用。它被指定调查 突触可塑性的丧失和非纤维性神经纤维引起的神经细胞死亡 Abeta寡聚体。低聚物在AD大脑中积累，目前最好的证据 表明它们有助于疾病进展，可能解释了 与淀粉样蛋白的不完全相关性。目标集中在三个关键属性， 寡聚体（对于Abeta衍生的可扩散配体，称为“ADDL”）。（一） ADDLs在一小时内抑制LTP，这是已知对任何疾病最快的反应之一。 Abeta的形式。(ii)ADDLs通过被阻断的机制杀死海马神经元 Fyn的种系敲除，一种与NMDA受体偶联的蛋白酪氨酸激酶 和破伤风诱导的LTP (iii)ADDL与细胞表面蛋白结合， 胰蛋白酶敏感性和聚集在点状“热点”。“目标是 了解ADDL神经毒性的分子基础。两个假设将是 评估。首先，ADDLs可能是小蛋白配体，通过 干扰Fyn信号转导，由特定毒素介导的结果 受体。或者，ADDL可能破坏细胞完整性， 特异性，产生细胞生理学的全局分解，包括 LTP丧失并最终导致细胞死亡。这些假设的预测将 通过提案的目标进行测试。 目标1. LTP或神经传递-ADDL的突触影响是否特异于 LTP或突触功能广泛受损。 目标2.可塑性的类型-ADDLs是否影响多种类型的神经元 可塑性，或只有破伤风诱导的LTP？ 目标3。分子影响-毒性是否源于ADDL对Fyn的影响，或者 ADDLs攻击替代或多个站点？ 目标4。细胞表面反应-ADDLs是否与特定的“毒素受体”结合， ADDL活性不依赖于独特的结合位点吗？ 这一应用的结果将为理解 在人脑中发现的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目标， 逆转，而不仅仅是减缓AD记忆损伤。

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.