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

描述(申请人提供)：在阿尔茨海默病(AD)中，β-淀粉样蛋白(Abeta)与年龄相关的认知功能下降、神经毒性和突触衰竭有关。在了解导致Aβ诱导的神经毒性的遗传因素和细胞机制方面已经取得了重大进展。然而，Abeta诱导的突触功能障碍在细胞死亡之前的机制还很不清楚，寻找安全有效的治疗干预措施来逆转Abeta相关的早期AD病理仍然是一个巨大的挑战。我们以前发现，急性应用Abeta抑制了海马长时程增强(LTP)，这是一种学习和记忆的突触模型，这种作用与细胞内钙信号的改变导致钙依赖的蛋白磷酸酶钙调神经磷酸酶激活有关。有趣的是，我们在几个模型系统中观察到神经营养素4和脑源性神经营养因子挽救了Abeta诱导的LTP和突触传递的缺陷。根据初步数据，我们假设神经营养素(NT)-Aβ相互作用的焦点是钙离子和钙调蛋白依赖的蛋白激酶II(CaMKII)。Abeta通过增强钙调神经磷酸酶的活性抑制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，NT还通过丝裂原活化蛋白激酶(MAPK)和磷脂酰肌醇激酶3(PI3K)这两个主要的激酶途径促进神经元的分化、存活和可塑性。这两个激酶通路可能通过增强AMPA受体功能或促进突触可塑性和神经元生存所需的基因转录而参与NT的拯救。这些假说将通过电生理、生化、免疫细胞化学和分子遗传学方法的组合进行检验。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置和机制；并通过各种药理学、分子和遗传操作来分析CaMKII、MAPK和PI3K在NT救援中的作用。这一结果可能为研究Aβ作用的突触机制和TrkB作用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.