Effects of intracranial rAAV.Neu3 on dementia and neuropathology

颅内 rAAV.Neu3 对痴呆和神经病理学的影响

• 批准号: 9335232
• 负责人: Francesca-Fang Liao
• 金额: $ 19万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335232
• 关键词: Affective; Affinity; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Antioxidants; Anxiety; Apoptosis; Apoptotic; Attenuated; Autopsy; Barbering; Behavioral; Behavioral Symptoms; Binding; Biological; Blood - brain barrier anatomy; Brain; Cell Death; Characteristics; Chronic; Clinical Trials; Cognition; Cognitive deficits; Complex; Data; Dementia; Disease; Dorsal; Event; Exhibits; GD3-synthase; Ganglioside GD3; Ganglioside GM1; Gangliosides; Glycolipids; Goals; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Infusion procedures; Injectable; Injection of therapeutic agent; Interneurons; Intraventricular Infusion; Knock-out; Learning; Mediating; Membrane; Memory; Memory Loss; Memory impairment; Modeling; Mus; Mutation; Nerve Degeneration; Neuraminidase; Neurobehavioral Manifestations; Neurons; Operative Surgical Procedures; Oxidative Stress; Parkinson Disease; Partner in relationship; Pathogenesis; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Positioning Attribute; Process; Property; Publishing; Pump; Recombinants; Reporting; Research; Role; Senile Plaques; Sensorimotor functions; Signal Transduction; Social Behavior; Synapses; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Ursidae Family; Vibrio cholerae; Vibrissae; Wild Type Mouse; abeta accumulation; abeta oligomer; adeno-associated viral vector; aged; arm; base; behavioral impairment; experience; experimental study; familial Alzheimer disease; gene therapy; habituation; improved; in vivo; indexing; insight; kainate; mouse model; neurochemistry; neuron loss; neuropathology; neuroprotection; neurotoxic; neurotoxicity; neurotrophic factor; neurotropin; novel; novel strategies; novel therapeutics; overexpression; prevent; social cognition; spatial memory; treatment strategy

A valid assessment of memory is perhaps the most important component of an endeavor to develop a novel treatment for Alzheimer's disease. However, memory is only one of the behavioral impairments that Alzheimer's patients exhibit. They also have affective and sensorimotor deficits, and problems with social behavior. The 5xFAD transgenic mouse bears five mutations known to cause familial Alzheimer's disease (FAD). Like other Alzheimer models, they exhibit profound cognitive deficits on tests of spatial learning and memory. Unlike other APP-overexpressing mice, the 5xFAD transgenics exhibit robust neurodegeneration by 9 months of age. However, the 5xFAD mice also show a host of other behavioral anomalies. For example, they exhibit abnormal social behavior toward their cage-mates and do not exhibit the barbering phenomenon characteristic of wild-type mice of the same strain. Although a published report shows that 5xFAD mice spend more time on open arms of a plus maze, indicative of decreased anxiety, we have shown that this is attributable to impaired habituation and degeneration of inhibitory interneurons in layer IV whisker barrels (putatively making closed arms aversive). All indices of anxiety in the 5xFAD transgenics were normal in our hands. In the studies proposed herein we will determine whether the ganglioside-specific murine sialidase Neu3 can enhance cognition, normalize social behavior, and prevent neuronal loss and amyloid-related neuropathology in the 5xFAD mice. We have shown previously that intraventricular infusion of sialidase from V. cholerae (VCS) protects against kainate-induced hippocampal damage. VCS hydrolyzes gangliosides and produces a brain ganglioside profile that is similar to that of GD3 synthase (GD3S) inhibition, which we have shown to be neuroprotective, reduce plaque, and improve memory in APP-overexpressing transgenics. Our preliminary data show that infusion of VCS for 8 weeks is neuroprotective and reduces plaque in 12-month-old 5xFAD mice, but complications with chronic infusion over months and the need for multiple surgeries to exchange pumps make this approach impractical. Instead, we developed a recombinant adeno-associated viral vector (rAAV) that produces neuraminidase 3 (Neu3) indefinitely. In the present study mice will be injected with rAAV.Neu3 or rAAV.eGFP control in the dorsal hippocampus at 4 months of age, when Aβ expression and memory impairments are already evident in 5xFAD transgenics. Social behavior, social cognition, and spatial memory will be assessed from 7 to 9 months, as well as control tests for anxiety and sensorimotor function. Post-mortem analyses will assess Alzheimer-related neuropathology and neurodegeneration. Successfully reducing amyloid burden, cell death, and memory impairments in the transgenic mice may provide insight into new treatment strategies for Alzheimer's disease--treatments that could reduce or prevent dementia and associated behavioral symptoms in Alzheimer patients.

对记忆的有效评估也许是奋进发展一部小说的最重要组成部分 阿尔茨海默病的治疗。然而，记忆只是行为障碍之一， 老年痴呆症患者的展览。他们也有情感和感觉运动缺陷，以及社交问题。 行为5xFAD转基因小鼠携带五种已知导致家族性阿尔茨海默病的突变 （FAD）。像其他阿尔茨海默病模型一样，他们在空间学习测试中表现出严重的认知缺陷， 记忆与其他APP过表达小鼠不同，5xFAD转基因小鼠表现出强烈的神经变性， 9个月大。然而，5xFAD小鼠也表现出许多其他行为异常。比如说， 它们对笼友表现出异常的社会行为， 具有相同品系的野生型小鼠的特征。尽管一份已发表的报告显示，5xFAD小鼠 更多的时间在一个十字迷宫的开放臂上，表明焦虑减少，我们已经表明，这是 归因于IV层须桶中抑制性中间神经元的习惯化受损和退化 （pupeles使闭合的手臂令人厌恶）。在我们的研究中，5xFAD转基因患者的所有焦虑指数都是正常的。 手在本文提出的研究中，我们将确定神经节苷脂特异性鼠唾液酸酶是否 Neu 3可以增强认知能力，使社会行为正常化，并防止神经元丢失和淀粉样蛋白相关的 在5xFAD小鼠中的神经病理学。我们以前已经表明，从脑室内输注唾液酸酶， 诉胆固醇（cholesterol，CHL）保护免受红藻氨酸盐诱导的海马损伤。β-淀粉酶水解神经节苷脂， 产生类似于GD 3合酶（GD 3S）抑制的脑神经节苷脂谱， 在APP过表达转基因动物中显示出神经保护作用、减少斑块和改善记忆。我们 初步数据显示，在12个月大的婴儿中， 5xFAD小鼠，但数月慢性输注的并发症以及需要多次手术以 交换泵使得这种方法不切实际。相反，我们开发了一种重组腺相关病毒 病毒载体（rAAV），其无限期地产生神经氨酸酶3（Neu 3）。在本研究中，小鼠将 在4月龄时在背侧海马中注射rAAV.Neu3或rAAV.eGFP对照，当Aβ 表达和记忆障碍在5xFAD转基因中已经很明显。社会行为，社会 认知和空间记忆将在7至9个月内进行评估，以及焦虑和 感觉运动功能尸检分析将评估阿尔茨海默病相关的神经病理学， 神经变性成功地减少淀粉样蛋白负担，细胞死亡，和记忆障碍， 转基因小鼠可能为阿尔茨海默病的新治疗策略提供见解-治疗方法， 可以减少或预防阿尔茨海默病患者的痴呆症和相关的行为症状。