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）：