ROLE OF HSP 110 IN TAUOPATHY

描述(由申请人提供)： 对退伍军人医疗保健的潜在影响是，创伤性脑损伤(TBI)是35岁以下人群死亡和残疾的主要原因，也是战斗中常见的疾病，会导致认知和社会问题的严重缺陷以及显著的淀粉样β蛋白(A？)生成。此外，有证据表明，脑外伤后淀粉样蛋白沉积增加，阿尔茨海默病(AD)的风险增加。然而，我们对阿尔茨海默病的治疗知识仍然不完整。阿尔茨海默病和其他神经病的神经病理特征包括老年斑和/或神经原纤维缠结(NFT)的积累，导致神经元退化。临床记录表明，定位于轴突的tau在与蛋白质功能障碍相关的神经退行性疾病中发挥着关键作用。热休克蛋白(HSPs)，如HSP110和HSP70i，在暴露于环境侮辱后高度表达。它们在神经元紊乱中的作用得到了研究的支持，研究表明几种热休克蛋白是NFTs的组成部分。因此，在含有tau的NFT中、在AD脑的神经性斑块中以及在脑损伤后的脑组织中都检测到了HSPs。我们的发现提供了热休克蛋白在神经退行性疾病中作用的直接指示，即hsp110-/-小鼠表现出与年龄相关的过度磷酸化tau(p-tau)积累和神经变性。我们还发现Hsp110、tau和Pin1异构酶在相同的复合体中，它们在小鼠中的缺失导致互变。由于Hsp110家族成员Hsp70已被证明参与细胞内淀粉样前体蛋白(APP)的处理，我们测试了hsp110-/-小鼠与表达突变APP(Tg2576+)的小鼠在体内是否表现出加速病理。结果表明，hsp110-/-Tg2576+小鼠确实比hsp110+/+Tg2576+小鼠更年轻地表现出神经性斑块，这有力地暗示了HSP110(和HSP70i)在体内AD病理中的作用。因此，了解HSP110和HSP70i阻止p-tau堆积、减少AD病理和影响脑损伤的机制是本次赠款申请的主题。我们推测，HSP110和HSP70i对tau的适当去磷酸化是关键的，在AD和脑损伤后具有保护作用，并防止神经元死亡。在我们提出的研究中，我们将确定HSP110、HSP70i、tau的表达和轴突内定位，或者HSP110和HSP70i是否为Pin1的底物。作为与肌萎缩侧索硬化症相关的神经退行性疾病的一个例子，我们将使用hsp110-/-Tg2576+小鼠来建立HSP110复合体在体内APP处理和A？产生中的作用；由于环境伤害后HSPs的表达增加，并且众所周知，由于脑创伤会增加发生AD的风险，我们将调查HSP110和HSP70i的存在是否在脑损伤后的恢复中起作用，如果短暂增加HSPs的水平加速脑损伤后的恢复；我们还将检查健康或AD患者的脑组织切片，以确定HSP110和HSP70i在老年斑块中的位置；最后，我们将使用接受脑创伤患者的脑脊液(CSF)来确定损伤后HSP110或HSP70i的水平是否与脑损伤的程度相关。 公共卫生相关性： 叙事热休克蛋白(HSP)保护细胞和生物体免受各种环境侮辱。然而，它们在体内神经退行性疾病中的作用仍然难以捉摸。我们发现，在阿尔茨海默病(AD)的小鼠模型中，HSP110(或HSP70i)的缺失会导致神经变性，并在比野生型小鼠年轻得多的年龄出现神经炎斑块。对退伍军人医疗保健的潜在影响是，创伤性脑损伤(TBI)是35岁以下人群死亡和残疾的主要原因，也是战斗中常见的疾病，会导致认知和社会问题的严重缺陷以及显著的淀粉样β蛋白(A？)生成。此外，有证据表明，脑外伤后淀粉样蛋白沉积增加，发展为AD的风险增加。在这项提案中，我们将试图了解HSP110和HSP70i在神经退行性变(如AD)中的作用；以及这些HSPs水平的一过性升高是否可以减少脑损伤后的病理；我们还将使用接受脑损伤的患者的脑脊液(CSF)来确定损伤后HSP110和HSP70i的水平是否与脑损伤的程度相关。

DESCRIPTION (provided by applicant): Potential Impact on Veteran's Heath care is that traumatic brain injury (TBI), which is the main cause of death and disability in people under 35 and a common occurrence in combat situations, leads to significant deficiency in cognitive and social problems and significant amyloid beta (A¿) generation. Furthermore, there is evidence of increased amyloid deposition and an increased risk of development of Alzheimer's disease (AD) following TBI. However, our knowledge regarding the treatment of AD is still incomplete. The neuropathological hallmarks of AD and other tauopathies include accumulation of senile plaques and/or neurofibrillary tangles (NFTs) that causes neurons to degenerate. Clinical records suggest that tau, which is localized in axons, plays a pivotal role in neurodegenerative disorders that are related to protein malfunction. Heat shock proteins (Hsps) such as Hsp110 and Hsp70i are highly expressed following exposure to environmental insults. Their role in neuronal disorders is supported by studies showing that several Hsps are components of NFTs. As such, Hsps have been detected in NFTs containing tau, in neuritic plaques of AD brain, and in the brain tissue following TBI. A direct indication of the role of Hsps in neurodegenerative disease is provided by our discovery that hsp110-/- mice exhibit an age-dependent accumulation of hyperphosphorylated tau (p-tau) and neurodegeneration. We have also found that Hsp110, tau, and Pin1 isomerase, whose deletion in mice leads to tauopathy are in the same complexes. Since the Hsp110 family member, Hsp70 has been shown to be involved in amyloid precursor protein (APP) processing in cells, we tested if hsp110-/- mice crossed with mice expressing a mutant APP (Tg2576+) exhibit accelerated pathology in vivo. Results indicate that indeed hsp110- /-Tg2576+ mice exhibit neuritic plaques at a younger age than the hsp110+/+Tg2576+ mice strongly suggesting a role for Hsp110 (and Hsp70i) in AD pathology in vivo. Therefore, understanding the mechanisms by which Hsp110 and Hsp70i prevent p-tau accumulation, reduce AD pathology, and impact TBI are the subject of this grant application. We hypothesize that Hsp110 and Hsp70i are critical for proper dephosphorylation of tau and are protective during AD and following TBI, and prevent neuronal death. In our proposed studies, we will determine the expression and intra-axonal localization of Hsp110, Hsp70i, tau, or if Hsp110 and Hsp70i are substrates of Pin1. As an example of neurodegenerative diseases associated with tauopathy, we will use hsp110-/-Tg2576+ mice to establish the role of Hsp110 complexes in APP processing and A¿ production in vivo; since the expression of Hsps increases following environmental insults and because TBI is known to increase the risk for developing AD, we will investigate if the presence of Hsp110 and Hsp70i play a role in the recovery from TBI, and if transiently increasing the levels of Hsps accelerate recovery following TBI; we will also examine the brain tissue sections from healthy or AD patients to determine the locations of Hsp110, Hsp70i in senile plaques; Finally, we will use cerebral spinal fluid (CSF) from the patients who have received TBI to determine whether the levels of Hsp110 or Hsp70i following injury correlates with the extent of brain injury. PUBLIC HEALTH RELEVANCE: Narrative Heat shock proteins (Hsp) protect cells and organisms against variety of environmental insults. However, their role in neurodegenerative diseases in vivo remains elusive. We have found that deletion of Hsp110 (or Hsp70i) in mice leads to neurodegeneration, and appearance of neuritic plaques at much younger age than the wild-type mice in the background of a mouse model of Alzheimer's Disease (AD). Potential Impact on Veteran's Heath care is that traumatic brain injury (TBI), which is the main cause of death and disability in people under 35 and a common occurrence in combat situations, leads to significant deficiency in cognitive and social problems and significant amyloid beta (A¿) generation. Furthermore, there is evidence of increased amyloid deposition and an increased risk of development of AD following TBI. In this proposal we will attempt to understand the role Hsp110 and Hsp70i in neurodegeneration (such as AD); and whether transient elevation in the levels of these Hsps reduces pathology following TBI; we will also use cerebral spinal fluid (CSF) from the patients who have received TBI to determine whether the levels of Hsp110 and Hsp70i following injury correlates with the extent of brain injury.