MECHANISMS OF OXIDATIVE SIGNALING TO AD NEUROPATHY

在第一个供资周期期间，项目2取得了几项重要发现。其中 结果如下：（1）多种信号激酶在体外被促氧化损伤持续激活， 体内脑缺血。(2)促氧化剂损伤导致至少三种蛋白质的持续减少 磷酸酶(3)这些信号激酶的持续激活将它们转化为死亡诱导激酶 导致氧化损伤、AD样神经病理学和神经元细胞死亡。(4)女性化和 非雌性化雌激素阻止促氧化剂诱导的蛋白质持续下调 磷酸酶和信号激酶的持续激活。此外，雌激素改善神经元死亡 和AD神经病理学由持续的激酶激活引起。(5)脑缺血引起磷酸酶 衰退、持续性激酶激活、进行性AD神经病理学、海马损伤和认知功能 年轻老鼠的下降。(6)蛋白磷酸酶的持续抑制导致认知能力下降， Tau病在年轻的大鼠。在证明了这些正常运作的信号通路之后， 持续激活，死亡诱导激酶途径，我们建议确定致病因素， (Aim 1）确定慢性磷酸酶抑制引起认知和LTP的机制 衰退和AD神经病理学;（目的2）确定持续激酶激活在AD中的作用 神经病理学;（目的3）确定AD中细胞周期蛋白依赖性激酶的诱导作用 神经病理学;并确定E2和非雌性化雌激素对胰岛素诱导的AD样 神经病理学;（目的4）确定雌激素改善这些变化的机制;和（ 目的5）探讨L型钙通道在雌激素上调蛋白磷酸酶中的作用。 总的来说，这些研究将确定氧化事件启动和促进的机制 AD神经病理学的进展以及雌激素可以拮抗这些作用的程度， 氧化应激

During the course of this first funding cycle, Project 2 made several important discoveries. Among these were the following: (1) Multiple signaling kinases are persistently activated by pro-oxidant insults in vitro and cerebral ischemia in vivo. (2) Pro-oxidant insults cause persistent reductions in at least three protein phosphatases. (3) Persistent activation of these signaling kinases converts them into death-inducing kinases that contribute to oxidative damage, AD-like neuropathology and neuronal cell death. (4) Both feminizing and non-feminizing estrogens prevent the pro-oxidant induced persistent down regulation of protein phosphatases and the persistent activation of signaling kinases. Also, estrogens ameliorate neuronal death and AD neuropathology causes by persistent kinase activation. (5) Cerebral ischemia causes phosphatase decline, persistent kinase activation, progressive AD neuropathology, hippocampal damage and cognitive decline in young rats. (6) Persistent inhibition of protein phosphatases causes cognitive decline and tauopathy in young rats. Having demonstrated these normally functioning signaling pathways become, with persistent activation, death-inducing kinase pathways, we propose to determine the causative factors by (Aim 1) determining the mechanism by which chronic phosphatase inhibition causes cognitive and LTP decline and AD neuropathology; (Aim 2) determining the role of persistent kinase activation in AD neuropathology; (Aim 3) determining the role of induction of cyclin-dependent kinases in AD neuropathology; and determining the effects of E2 and non-feminizing estrogens on insult-induced AD-like neuropathology; (Aim 4) determining the mechanism by which estrogens ameliorate these changes; and ( Aim 5) determining the role of L-type Ca2+ channels in the estrogen up regulation of protein phosphatases. Collectively, these studies will determine the mechanism(s) by which oxidative events initiate and contribute to the progression of AD neuropathology and the extent to which estrogen can antagonize these effects of oxidative stress.