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）中与年龄相关的认知能力下降、神经毒性和突触功能衰竭有关。在了解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，abeta诱导的突触功能障碍的机制在很大程度上是未知的，寻找安全有效的治疗干预措施来逆转与abeta相关的早期AD病理仍然是一个巨大的挑战。我们之前的研究表明，急性应用Abeta抑制海马长期增强（LTP），这是一种学习和记忆的突触模型，这种作用与细胞内Ca2+信号的改变有关，导致Ca2+依赖性蛋白磷酸酶钙调磷酸酶的激活。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β诱导的LTP和突触传递缺陷。根据初步数据，我们假设神经营养因子(NT)- β相互作用的焦点是Ca2+和钙调素依赖性蛋白激酶II （CaMKII）。Abeta通过增强钙调磷酸酶活性抑制CaMKII的激活，而NT通过刺激CaMKII和增强AMPA型谷氨酸受体的功能和突触靶向来抵消Abeta的作用。此外，已知NT通过丝裂原活化蛋白激酶（MAPK）和磷酸肌苷激酶3 （PI3K）两种主要激酶途径促进神经元分化、存活和可塑性。这两种激酶途径可能通过增强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促进NT的拯救。这些假设将使用电生理，生化，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- β相互作用在调节海马突触可塑性的多种形式；确定突触位点和它们对立作用的机制；并利用各种药理学、分子和遗传操作分析CaMKII、MAPK和PI3K在NT抢救中的作用。该结果可能为Abeta作用的突触机制和trkb作用的NT治疗早期AD的潜力提供新的见解。

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.