Neurotrophin Rescue of Beta Amyloid (AB) -induced Synaptic Dysfunction

描述（由申请人提供）：β-淀粉样蛋白（Abeta）与阿尔茨海默病（AD）中年龄相关的认知衰退、神经毒性和突触失效相关。在理解导致Abeta诱导的神经毒性的遗传因素和细胞机制方面取得了重大进展。然而，在细胞死亡之前负责Abeta诱导的突触功能障碍的机制在很大程度上是未知的，并且找到安全有效的治疗干预来逆转Abeta相关的早期AD病理仍然是一个巨大的挑战。我们以前表明，急性应用Abeta抑制海马长时程增强（LTP），学习和记忆的突触模型，这种效果与改变细胞内Ca 2+信号转导，导致激活的Ca 2+依赖性蛋白磷酸酶钙调磷酸酶。有趣的是，我们在几个模型系统中观察到神经营养因子4和脑源性神经营养因子挽救了Abeta诱导的LTP和突触传递缺陷。基于初步数据，我们假设神经营养因子（NT）- Abeta相互作用的焦点是Ca 2+和钙调蛋白依赖性蛋白激酶II（CaMKII）。Abeta通过增强的钙调磷酸酶活性抑制CaMKII活化，而NT通过刺激CaMKII并增强AMPA型谷氨酸受体的功能和突触靶向来抵消Abeta作用。此外，NT通过两条主要的激酶途径，丝裂原活化蛋白激酶（MAPK）和磷酸肌醇激酶3（PI 3 K）促进神经元分化、存活和可塑性。这两个激酶途径可能有助于通过增强AMPA受体功能或促进突触可塑性和神经元存活所需的基因转录来拯救NT。这些假设将使用电生理学，生物化学，免疫细胞化学和分子遗传学方法的组合进行测试。我们将进一步研究NT-Abeta在调节多种形式的海马突触可塑性中的相互作用;确定其相反作用的突触位点和机制;并使用各种药理学、分子和遗传操作分析CaMKII、MAPK和PI 3 K在NT拯救中的作用。这些结果可能为Abeta作用的突触机制和trkB作用的NT对早期AD的治疗潜力提供新的见解。

DESCRIPTION (provided by applicant): Beta-Amyloid (Abeta) is associated with age-related cognitive decline, neurotoxicity and synaptic failure in Alzheimer's disease (AD). Significant progress has been made in understanding the genetic factors and cellular mechanisms contributing to Abeta-induced neurotoxicity. However, the mechanisms responsible for Abeta-induced synaptic dysfunction prior to cell death are largely unknown, and finding safe and effective therapeutic interventions to reverse Abeta-related early AD pathology remains a great challenge. We previously showed that acute application of Abeta inhibited hippocampal long-term potentiation (LTP), a synaptic model of learning and memory, and that this effect was associated with altered intracellular Ca2+ signaling leading to activation of a Ca2+-dependent protein phosphatase calcineurin. Interestingly, we observed in several model systems that neurotrophin 4 and brain-derived neurotrophic factor rescued Abeta- induced deficits in LTP and synaptic transmission. Based on the preliminary data, we hypothesize that a focal point for the neurotrophin (NT)- Abeta interaction is Ca2+ and calmodulin-dependent protein kinase II (CaMKII). Abeta inhibits CaMKII activation via enhanced calcineurin activity, whereas NT counteracts Abeta action by stimulating CaMKII and enhancing the function and synaptic targeting of the AMPA type of glutamate receptors. In addition, NT is known to promote neuronal differentiation, survival and plasticity through two major kinase pathways, mitogen-activated protein kinase (MAPK) and phosphoinositide kinase 3 (PI3K). These two kinase pathways may contribute to the NT rescue by enhancing AMPA receptor function or promoting gene transcription required for both synaptic plasticity and neuronal survival. These hypotheses will be tested using a combination of electrophysiological, biochemical, immunocytochemical and molecular genetic approaches. We will further examine NT- Abeta interactions in regulating multiple forms of hippocampal synaptic plasticity; determine the synaptic locus and mechanisms underlying their opposing effects; and analyze the role of CaMKII, MAPK and PI3K in the NT rescue using various pharmacological, molecular and genetic manipulations. The results may provide new insights into synaptic mechanisms for Abeta action and the therapeutic potentials of trkB-acting NT for early AD.