ROLE OF HSP 110 IN TAUOPATHY

HSP 110 在 Tauopathy 中的作用

• 批准号: 7796230
• 负责人: NAHID F MIVECHI
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796230
• 关键词: Acute Brain Injuries; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Appearance; Applications Grants; Axon; Behavioral; Brain; Brain Injuries; Caring; Cause of Death; Cells; Cerebrospinal Fluid; Cessation of life; Clinical; Cognitive; Complex; Development; Disease; Down Syndrome; Event; Exhibits; Exposure to; Family member; Future; Generations; Goals; Heat shock proteins; Impaired cognition; In Vitro; Inherited; Injury; Isomerase; Knowledge; Life; Location; Microtubule-Associated Proteins; Microtubules; Molecular; Molecular Chaperones; Molecular Machines; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organism; Pathology; Patients; Pattern; Pick Disease of the Brain; Play; Production; Protein Dephosphorylation; Proteins; Records; Recovery; Risk; Role; Senile Plaques; Social Problems; Tauopathies; Testing; Tg2576; Therapeutic; Toxic effect; Traumatic Brain Injury; Variant; Veterans; Wild Type Mouse; age related; amyloid precursor protein processing; brain tissue; combat; corticobasal degeneration; disability; hyperphosphorylated tau; in vivo; mouse model; mutant; pre-clinical; prevent; protein degradation; protein misfolding; public health relevance; response; tau Proteins; tau aggregation

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.

描述（由申请人提供）： 对退伍军人健康护理的潜在影响是，创伤性脑损伤 (TBI) 是 35 岁以下人群死亡和残疾的主要原因，在战斗情况下很常见，它会导致认知和社会问题的严重缺乏以及β淀粉样蛋白的显着缺乏。此外，有证据表明 TBI 后淀粉样蛋白沉积增加，患阿尔茨海默病 (AD) 的风险增加。然而，我们对 AD 治疗的了解仍然不完整。其他 tau 蛋白病包括导致神经元退化的老年斑和/或神经原纤维缠结 (NFT) 的积累。临床记录表明，位于轴突中的 tau 蛋白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。研究表明，Hsp110 和 Hsp70i 等蛋白质 (Hsp) 在暴露于环境损伤后会高度表达，它们在神经元疾病中的作用得到了支持。一些热休克蛋白是 NFT 的组成部分，因此，在含有 tau 蛋白的 NFT 中、在 AD 大脑的神经炎斑块中以及在 TBI 后的脑组织中都检测到了热休克蛋白，我们的发现直接表明了热休克蛋白在神经退行性疾病中的作用。 hsp110-/- 小鼠表现出年龄依赖性的过度磷酸化 tau (p-tau) 积累和神经变性。 tau 和 Pin1 异构酶（其在小鼠中的缺失会导致 tau 病）处于相同的复合物中。由于 Hsp110 家族成员，Hsp70 已被证明参与细胞中的淀粉样前体蛋白 (APP) 加工，因此我们测试了 hsp110-/- 是否存在。与表达突变 APP (Tg2576+) 的小鼠杂交的小鼠在体内表现出加速的病理学结果表明，hsp110-/-Tg2576+ 小鼠确实表现出加速的病理变化。比 hsp110+/+Tg2576+ 小鼠更年轻时出现的神经炎斑块强烈表明 Hsp110（和 Hsp70i）在体内 AD 病理学中的作用。因此，了解 Hsp110 和 Hsp70i 防止 p-tau 积累的机制，可以减少 AD 病理学。和影响 TBI 是本次拨款申请的主题，我们勇敢地说 Hsp110 和 Hsp70i 对于适当的去磷酸化至关重要。 tau 在 AD 期间和 TBI 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，或者以 Hsp110 和 Hsp70i 是否是 Pin1 的底物为例。对于与 tau 蛋白病相关的神经退行性疾病，我们将使用 hsp110-/-Tg2576+ 小鼠来确定 Hsp110 的作用APP 处理和 A¿由于 Hsps 的表达在环境损伤后增加，并且已知 TBI 会增加患 AD 的风险，因此我们将研究 Hsp110 和 Hsp70i 的存在是否在 TBI 的恢复中发挥作用，以及是否会暂时增加 TBI 的表达。 Hsps 水平加速 TBI 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、Hsp70i 在老年斑中的位置；来自接受过 TBI 的患者的脊髓液 (CSF)，以确定损伤后 Hsp110 或 Hsp70i 的水平是否与脑损伤的程度相关。 公共卫生相关性： 叙述 热休克蛋白 (Hsp) 可以保护细胞和生物体免受各种环境损害，但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，小鼠体内 Hsp110（或 Hsp70i）的缺失会导致神经退行性病变和神经症的出现。在阿尔茨海默病 (AD) 小鼠模型中，比野生型小鼠年轻得多的斑块对退伍军人健康护理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，在战斗情况下很常见，它会导致认知和社会问题的严重缺陷以及大量淀粉样蛋白 (A¿) 的产生。此外，有证据表明TBI 后淀粉样蛋白沉积增加，AD 发生风险增加。在本提案中，我们将尝试了解 Hsp110 和 Hsp70i 在神经变性（例如 AD）中的作用，以及这些 Hsp 水平的短暂升高是否会减轻病理学。 TBI 后；我们还将使用接受过 TBI 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程度相关。