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）： 对退伍军人的卫生保健的潜在影响是，创伤性脑损伤（TBI）是35岁以下的人死亡和残疾的主要原因，并且在战斗情况下发生了常见的发生，导致认知和社会问题的严重缺陷以及明显的淀粉样蛋白β（A a。）一代。此外，有证据表明淀粉样蛋白沉积增加，而在TBI后，阿尔茨海默氏病（AD）的发展风险增加。但是，我们关于AD处理的知识仍然不完整。 AD和其他Tauopath的神经病理学标志包括导致神经元退化的老年斑块和/或神经原纤维缠结（NFTS）的积累。临床记录表明，位于轴突中的TAU在与蛋白质功能障碍有关的神经退行性疾病中起关键作用。暴露于环境伤害后，热休克蛋白（HSP）（例如HSP110和HSP70I）高度表达。研究表明，有几个HSP是NFT的组成部分，它们在神经元疾病中的作用得到了支持。因此，在包含tau的NFT，AD脑的神经质斑块以及TBI后的脑组织中检测到了HSP。我们的发现提供了HSP110 - / - 小鼠在神经退行性疾病中的作用的直接指示，表现出了年龄依赖性的热磷酸化tau（P-TAU）和神经变性的积累。我们还发现，HSP110，TAU和PIN1异构酶，它们在小鼠中的缺失导致双性异性病在同一复合物中。由于HSP110家族成员，HSP70已被证明与细胞中的淀粉样蛋白前体蛋白（APP）加工有关，我们测试了是否与表达突变APP（TG2576+）的小鼠交叉的Hsp110 - / - 小鼠在Vivo中暴露了加速病理学。结果表明，与HSP110+ /+ TG2576+小鼠相比，HSP110- /-TG2576+小鼠在VIVO中强烈暗示HSP110（和HSP70I）的作用。因此，了解HSP110和HSP70I防止P-TAU积累，减少AD病理和影响TBI的机制是本赠款应用的主题。我们假设Hsp110和Hsp70i对于适当的tau去磷酸化至关重要，并且在AD和TBI之后受到保护，并预防神经元死亡。在我们提出的研究中，我们将确定Hsp110，Hsp70i，Tau或HSP110和HSP70I的表达和轴内定位是PIN1的底物。作为与Tauopathy相关的神经退行性疾病的一个例子，我们将使用HSP110 - / - TG2576+小鼠来确定HSP110复合物在App Processing和Vivo中的生产中的作用；由于HSP的表达在环境伤害后增加，并且已知TBI增加了发展AD的风险，因此我们将研究HSP110和HSP70I的存在是否在从TBI中恢复中起作用，以及是否会暂时提高TBI后HSPS加速恢复的水平；我们还将检查健康或AD患者的脑组织切片，以确定HSP110，HSP70I在老年斑块中的位置；最后，我们将使用接受TBI的患者使用脑脊髓液（CSF），以确定损伤后HSP110或HSP70I的水平是否与脑损伤程度相关。 公共卫生相关性： 叙事热休克蛋白（HSP）保护细胞和生物免受各种环境侮辱。但是，它们在体内的神经退行性疾病中的作用仍然难以捉摸。我们发现，小鼠中Hsp110（或Hsp70i）的缺失会导致神经变性，而在阿尔茨海默氏病小鼠模型的背景下，与野生型小鼠相比，在年轻的年龄中，神经性斑块出现。对退伍军人的卫生保健的潜在影响是，创伤性脑损伤（TBI）是35岁以下的人死亡和残疾的主要原因，并且在战斗情况下发生了常见的发生，导致认知和社会问题的严重缺陷以及明显的淀粉样蛋白β（A a。）一代。此外，有证据表明淀粉样蛋白沉积增加和TBI后AD发展的风险增加。在此提案中，我们将尝试了解HSP110和HSP70I在神经变性中的作用（例如AD）；以及这些HSP水平的短暂升高是否会降低TBI后的病理；我们还将使用接受TBI的患者的脑脊髓液（CSF），以确定损伤后HSP110和HSP70I的水平是否与脑损伤程度相关。