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，也是战斗情况下常见的情况，会导致认知和社会问题的严重缺陷，并导致大量淀粉样蛋白β（A ²）生成。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治疗的认识仍然不完整。AD和其他tau蛋白病的神经病理学标志包括老年斑和/或神经元缠结（NFT）的积累，其导致神经元退化。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起着关键作用。热休克蛋白（Hsps）如Hsp 110和Hsp 70 i在暴露于环境损伤后高度表达。它们在神经元疾病中的作用得到了研究的支持，研究表明几种Hsp是NFT的组分。因此，已经在含有tau的NFT中、在AD脑的神经炎斑块中以及在TBI后的脑组织中检测到Hsps。我们发现hsp 110-/-小鼠表现出年龄依赖性的过度磷酸化tau（p-tau）和神经退行性疾病的积累，这一发现提供了Hsps在神经退行性疾病中作用的直接指示。我们还发现，Hsp 110，tau和Pin 1异构酶，其在小鼠中的缺失导致tau蛋白病是在相同的复合物。由于热休克蛋白110家族成员，热休克蛋白70已被证明参与淀粉样前体蛋白（APP）的细胞加工，我们测试了如果热休克蛋白110-/-小鼠与小鼠杂交表达突变APP（Tg 2576+）表现出加速体内病理。结果表明，hsp 110- /-Tg 2576+小鼠确实在比hsp 110 +/+ Tg 2576+小鼠更年轻的年龄表现出神经炎斑块，这强烈表明Hsp 110（和Hsp 70 i）在体内AD病理学中的作用。因此，了解Hsp 110和Hsp 70 i防止p-tau积累、减少AD病理学和影响TBI的机制是本资助申请的主题。我们假设Hsp 110和Hsp 70 i对tau蛋白的适当去磷酸化至关重要，在AD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Hsp 110，Hsp 70 i，tau的表达和轴突内定位，或者Hsp 110和Hsp 70 i是否是Pin 1的底物。作为与tau蛋白病相关的神经退行性疾病的一个例子，我们将使用hsp 110-/-Tg 2576+小鼠来确定Hsp 110复合物在体内APP加工和A？产生中的作用;由于Hsps的表达在环境损伤后增加并且由于已知TBI会增加发生AD的风险，我们将研究Hsp 110和Hsp 70 i的存在是否在TBI的恢复中起作用，以及瞬时增加Hsps的水平是否加速TBI后的恢复;我们还将检测健康人和AD患者的脑组织切片，以确定Hsp 110、Hsp 70 i在老年斑中的定位;最后，我们将使用脑脊髓液（CSF）从谁收到了TBI的患者，以确定是否Hsp 110或Hsp 70 i的水平与脑损伤的程度相关。 公共卫生相关性： 热休克蛋白（Hsp）保护细胞和生物体免受各种环境的伤害。然而，它们在体内神经退行性疾病中的作用仍然难以捉摸。我们已经发现，在阿尔茨海默病（AD）小鼠模型的背景下，小鼠中Hsp 110（或Hsp 70 i）的缺失导致神经变性，并且在比野生型小鼠小得多的年龄出现神经炎斑块。对退伍军人健康护理的潜在影响是创伤性脑损伤（TBI），这是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，导致认知和社会问题的严重缺陷以及淀粉样蛋白β（A？）的产生。此外，有证据表明TBI后淀粉样蛋白沉积增加，AD发展风险增加。在本提案中，我们将尝试了解Hsp 110和Hsp 70 i在神经退行性疾病（例如AD）中的作用;以及这些Hsps水平的短暂升高是否会减轻TBI后的病理学;我们还将使用接受TBI的患者的脑脊髓液（CSF）来确定损伤后Hsp 110和Hsp 70 i的水平是否与脑损伤的程度相关。