CA2+ SIGNALING-- ROLE IN ABETA-INDUCED MEMORY DEFICITS

描述（改编自申请人的摘要）：虽然它通常是 同意淀粉样蛋白13（A，B）肽在大脑中的积累有助于 阿尔茨海默病（AD）的发病机制，细胞机制， A13与AD痴呆症的联系尚未得到解决。我们的研究表明， 用A、B或其活性片段A、B2在亚神经毒性下35灌注 浓度强烈抑制的早期和晚期阶段的长期 增强（LTP）在大鼠海马脑片的齿状回，和 钙调神经磷酸酶可挽救A，13对LTP晚期的损伤 抑制剂的此外，急性应用A132s 35导致快速但 细胞内瞬时钙升高和钙振荡增强 海马神经元我们在此建议进一步调查 之间的A，关于诱导的Ca2+信号转导的改变和抑制 海马LTP推测A，约诱导细胞内Ca2 + 升高和随后的钙调磷酸酶激活，钙/钙调蛋白依赖性 蛋白磷酸酶在LTP损伤中起关键作用。Ca2+瞬变 可促进NMDA受体的Ca~（2+）依赖性失活或脱敏 通道，抑制LTP的诱导。钙调神经磷酸酶的激活也可能 改变磷酸酶级联和几种蛋白激酶之间的平衡 系统，导致LTP门控机制的变化和/或 cAMP-反应元件结合蛋白（CREB）的磷酸化状态。这些 信令变化又可以抑制LTP的后续分量。因此经由 改变的Ca 2+信号传导A，13干扰细胞的早期和晚期组分， LTP，这可能是阿尔茨海默氏症记忆缺陷的细胞基础 疾病电生理学、免疫细胞化学和神经化学方法 将被用来检验这一假设。建议的具体目标是：1） 进一步表征A、B对早期和晚期 检测A，13是否抑制NMDA受体， 通道的突触后神经元抑制LTP诱导; 3），以确定 是否A，关于诱导的Ca2+升高和钙调神经磷酸酶激活是负责 4）为了检测Ap是否激活NMDA通道， 钙调神经磷酸酶/PP1级联损害LTP的中间期;和5） 为了确定A，13是否通过调节CREB的磷酸化来改变CREB的磷酸化， 钙调神经磷酸酶依赖性机制，从而抑制晚期LTP。

DESCRIPTION (adapted from applicant's abstract): Although it is generally agreed that accumulation of amyloid 13 (A,B) peptides in the brain contributes to the pathogenesis of Alzheimer's disease (AD), the cellular mechanisms that link A13 to AD dementia remain unresolved. Our studies showed that brief perfusion with A,B or its active fragment A,B2s 35 at subneurotoxic concentrations strongly inhibited the early and late phase of long-term potentiation (LTP) in the dentate gyrus of rat hippocampal slices, and impairment of late-phase LTP by A,13 could be rescued by calcineurin inhibitors. Furthermore, acute application of A132s 35 resulted in rapid but transient intracellular Ca2+ rises and enhanced Ca2+ oscillations in cultured hippocampal neurons. We have proposed here to further investigate the link between A, about induced alterations in Ca2+ signaling and inhibition of hippocampal LTP. It is hypothesized that A, about induced intracellular Ca2+ rises and subsequent activation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, play the key role in LTP impairment. The Ca2+ transient may facilitate Ca2+-dependent inactivation or desensitization of NMDA receptor channels, suppressing induction of LTP. Activation of calcineurin may also shift the balance between a phosphatase cascade and several protein kinase systems, leading to changes in a LTP gating mechanism and/or alterations in the phosphorylation state of cAMP-response element binding protein (CREB). These signaling changes can in turn suppress the later components of LTP. Thus, via altered Ca2+ signaling A,13 interferes with both early and late components of LTP, which forms a possible cellular basis for memory deficits in Alzheimer's disease. Electrophysiological, immunocytochemical and neurochemical approaches will be used to test this hypothesis. The proposed Specific Aims are: 1) To further characterize the inhibitory action of A,B on both early and late components of dentate LTP; 2) To examine whether A,13 inhibits NMDA receptor channels of postsynaptic neurons to suppress LTP induction; 3) To determine whether A, about induced Ca2+ rises and calcineurin activation are responsible for inhibition of NMDA channels; 4) To deter aboutnine whether Ap activates the calcineurin/PP1 cascade to impair the inter aboutnediate phase of LTP; and 5) To determine whether A,13 alters CREB phosphorylation via a calcineurin-dependent mechanism, thus suppressing the late-phase LTP.