Restorative gene therapy on hippocampal spino-dendritic abnormalities: a focus on Alzheimer’s disease

海马棘树突异常的恢复性基因治疗：关注阿尔茨海默病

基本信息

批准号：
10343842
负责人：
RUTH M BARRIENTOS
金额：
$ 19.83万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343842
关键词：
3xTg-AD mouse Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Behavioral Behavioral Paradigm Brain region Candidate Disease Gene Characteristics Clinical Clinical Trials Confocal Microscopy Data Dementia Dendrite Regeneration Dendrites Dendritic Spines Disease Elderly Exhibits Exposure to Female Genes Goals Golgi Apparatus Hippocampus (Brain)Immunohistochemistry Impaired cognition Impairment In Vitro Injections Intracellular Signaling Proteins Knowledge Laboratories Learning Locomotion Long-Term Potentiation Maintenance Measurement Measures Mediating Mediator of activation protein Memory Memory Loss Memory impairment Mission Morphogenesis Morphology Motor Mouse Strains Mus Mutation Natural regeneration Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurotoxins Pathologic Pediatric Hospitals Pharmaceutical Preparations Phosphoproteins Process Proteins Public Health Quality of life Research Role Semaphorin-3A Senile Plaques Serotyping Stains Structure Synapses Synaptic plasticity Testing Therapeutic Transgenic Mice Transgenic Organisms United States National Institutes of Health Vertebral column Viral Wild Type Mouse Work adeno-associated viral vector cognitive function conditioned fear density design effective intervention effective therapy experience gene therapy generalized anxiety healthy aging improved in vivo innovation male morris water maze mouse model neuropathology novel overexpression presenilin-1 preservation prevent repaired response spatial memory therapeutically effective vector

项目摘要

SUMMARY/ABSTRACT There are currently no effective treatments to prevent, delay, or reverse the memory deficits and neuropathological alterations—specifically dendritic damage and synaptic loss—associated with Alzheimer’s disease (AD). Without an effective treatment soon, many more millions of older adults will continue to suffer from this devastating disease. Thus, there is a critical need to investigate novel molecules/mechanisms involved in the maintenance and regeneration of dendrites and their spines for the purpose of rescuing cognitive functions. The long-term goal is to develop an effective treatment to prevent or halt AD. The overall objective of this application is to determine the potential of a recently identified phosphoprotein, CRMP3 (collapsing response mediator protein 3), to ameliorate dendritic abnormalities and/or rescue memory deficits in two distinct mouse models with AD-like characteristics. 3xTg-AD mice are one of the most commonly used mouse models of AD. They harbor 3 mutations (APP, PSEN1, and MAPT) that result in the accumulation of plaques and tangles, abnormalities in dendritic and synaptic structures, and significant cognitive impairments. CRMP3-/- mice exhibit dystrophic hippocampal dendrites and profoundly impaired synaptic plasticity (LTP). Importantly, overexpressing the CRMP3 protein in hippocampal neurons, in vitro, dramatically enhances dendritic formation. The central hypothesis is that over-expressing CRMP3, in vivo, will prevent further dendritic degeneration and/or evoke dendritic regrowth and remodeling of spines in otherwise degenerating hippocampal neurons, thus preserving or rescuing memory function. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicants’ laboratories. This hypothesis will be tested by pursuing two specific aims: 1) Determine the extent to which in vivo over-expression of CRMP3 enhances hippocampal dendritic complexity and spine structure in CRMP3-/- and 3xTg-AD mice; and 2) Determine the extent to which in vivo over-expression of CRMP3 affects hippocampal-dependent memory function in CRMP3-/- and 3xTg-AD mice. Under the first aim, adeno-associated viral vector serotype 9 (AAV9) gene therapy will be used to overexpress CRMP3 in the hippocampus of these two AD-like mouse models and its effects on AD-associated spino-dendritic abnormalities will be examined. Under the second aim, the extent to which CRMP3 gene therapy can ameliorate contextual and spatial memory function will be measured using two behavioral paradigms (contextual fear conditioning and Morris water maze). The approach is innovative because CRMP3 is a little-known protein with tremendous potential to repair and regenerate dystrophic and damaged spines and dendrites. The proposed research is significant because it is expected to advance knowledge about a protein with the robust capacity to slow, halt, or even reverse early AD processes that may be precursors to deep dementia, thus profoundly improving quality of life. Ultimately, such findings have the potential to move to clinical trials as a treatment for AD.

摘要/摘要目前尚无有效的治疗方法来预防、延缓或逆转记忆缺陷和与阿尔茨海默病相关的神经病理学改变，特别是树突损伤和突触丧失如果不能尽快找到有效的治疗方法，数以百万计的老年人将继续遭受这种疾病的困扰。因此，迫切需要研究参与这种破坏性疾病的新分子/机制。树突及其脊柱的维持和再生，以挽救认知功能。长期目标是开发一种有效的治疗方法来预防或阻止 AD。该应用的目的是确定最近发现的磷蛋白 CRMP3（崩溃反应）的潜力介导蛋白 3)，改善两只不同小鼠的树突异常和/或挽救记忆缺陷 3xTg-AD 小鼠是最常用的 AD 小鼠模型之一。它们含有 3 种突变（APP、PSEN1 和 MAPT），导致斑块和缠结的积累， CRMP3-/- 小鼠表现出树突和突触结构异常以及显着的认知障碍。营养不良的海马树突和严重受损的突触可塑性（LTP）。在体外，海马神经元中的 CRMP3 蛋白可显着增强树突的形成。假设体内过度表达 CRMP3 将阻止进一步的树突变性和/或诱发退化海马神经元中的树突再生和脊柱重塑，从而保留或拯救记忆功能这一假设是在强有力的初步数据的基础上提出的。该假设将通过追求两个具体目标进行测试：1）确定 CRMP3 体内过度表达增强海马树突复杂性的程度 CRMP3-/- 和 3xTg-AD 小鼠的脊柱结构；2) 确定体内过度表达的程度 CRMP3 影响 CRMP3-/- 和 3xTg-AD 小鼠的海马依赖性记忆功能。腺相关病毒载体血清型 9 (AAV9) 基因治疗将用于在这两种 AD 样小鼠模型的海马及其对 AD 相关棘树突异常的影响将在第二个目标下检查 CRMP3 基因治疗可以在多大程度上改善环境。空间记忆功能将使用两种行为范式（情境恐惧调节和 Morris 水迷宫）该方法是创新的，因为 CRMP3 是一种鲜为人知的蛋白质，但具有巨大的作用。修复和再生营养不良和受损的脊柱和树突的潜力拟议的研究是。意义重大，因为它有望增进人们对一种蛋白质的认识，这种蛋白质具有减缓、停止、甚至逆转可能是深度痴呆症前兆的早期 AD 过程，从而显着提高质量最终，这些发现有可能进入临床试验，作为 AD 的治疗方法。