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Chronic sialidase effects on amyloid aggregation and associated pathology

慢性唾液酸酶对淀粉样蛋白聚集及相关病理的影响

基本信息

批准号：
7927055
负责人：
MICHAEL P MCDONALD
金额：
$ 46.07万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7927055
关键词：
Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Precursor Apoptotic Attenuated Binding Biological Birth Brain Cell Death Chronic Complex Development Disease Evaluation Event GD1a ganglioside GD3-synthase Gangliosides Genes Glycolipids Goals Human Hydrolysis Impaired cognition In Vitro Intervention Knock-out Knockout Mice Learning Membrane Memory Memory impairment Modeling Mus National Institute of Neurological Disorders and Stroke National Institute on Aging Nerve Degeneration Neuraminidase Neurobehavioral Manifestations Neurons Oxidative Stress Pathogenesis Pathology Patients Pharmaceutical Preparations Positioning Attribute Process Research Resistance Role Senile Plaques Series Staging Testing Therapeutic Transgenes Transgenic Mice Work base disease characteristic experience gene therapy in vivo insight mouse model mutant neurochemistry neuropathology neurotoxic neurotoxicity novel novel strategies novel therapeutics presenilin prevent research study therapeutic target treatment strategy

项目摘要

Alzheimer’s disease is characterized by the aggregation of β-amyloid (Aβ) protein in the brain, widespread neurodegeneration, and cognitive decline. Our work focuses on amelioration of Alzheimer's pathology by reducing or simplifying the major brain gangliosides and the pro-apoptotic ganglioside GD3. Gangliosides are glycosphingolipids richly expressed in brain tissue. We have previously shown that knocking out the gene that codes for GD3S (St8sia1) drastically reduces Aβ aggregation and oxidative stress, and prevents memory deficits in mice carrying mutant human transgenes for amyloid precursor protein (App) and presenilin 1 (Psen1), genes known to cause Alzheimer's disease. In addition, primary neurons from GD3S knockout mice are resistant to Aβ-induced cell death. However, GD3S is absent from birth in these mice, and they lack many of the gangliosides critical for normal brain development. The objective of the proposed studies is to determine whether in vivo degradation of b-series gangliosides and GD1a is as effective as knocking out GD3S in alleviating features of Alzheimer's disease in the 5xFAD mouse model of Alzheimer's disease. The general hypothesis of the proposed research is that vibrio cholerae sialidase (VCS) will successfully reduce plaque formation, block cell death, and prevent memory impairments in adult mutant mice. In the proposed experiments, VCS will be chronically administered to assess efficacy in 5xFAD transgenic mice. Cognition, anxiety, and sensorimotor function will be assessed in all mice. Post-mortem analyses will include a full complement of assays to assess Alzheimer-related neuropathology and cell death. Successfully reducing amyloid burden, cell death, and memory impairment in the transgenic mice may provide insight into new treatment strategies for Alzheimer’s disease—treatments that could reduce or prevent neurodegeneration and dementia in Alzheimer patients.

阿尔茨海默病的特征是β-淀粉样蛋白（Aβ）在脑内聚集，广泛分布于神经退化和认知能力下降我们的工作重点是改善阿尔茨海默病的病理，减少或简化主要脑神经节苷脂和促凋亡神经节苷脂GD 3。神经节是脑组织中丰富表达的鞘糖脂。我们之前已经证明，敲除编码GD 3S（St 8 sia 1）的基因可显著降低Aβ聚集和氧化应激，携带淀粉样前体蛋白（App）突变型人类转基因小鼠的记忆缺陷，早老素1（Psen 1），已知导致阿尔茨海默病的基因。此外，GD 3S的原代神经元敲除小鼠对Aβ诱导的细胞死亡具有抗性。然而，GD 3S在这些小鼠中从出生起就不存在，并且它们缺乏许多对大脑正常发育至关重要的神经节苷脂。建议的目标研究的目的是确定b系列神经节苷脂和GD 1a的体内降解是否与在阿尔茨海默病的5xFAD小鼠模型中敲除GD 3S以减轻阿尔茨海默病的特征疾病拟议研究的一般假设是霍乱弧菌唾液酸酶（VCS）将成功减少噬斑形成，阻止细胞死亡，并防止成年突变体记忆障碍小鼠在拟定的实验中，将长期给予CYP 1A 1，以评估5xFAD的疗效。转基因小鼠。将在所有小鼠中评估认知、焦虑和感觉运动功能。验尸分析将包括一个完整的分析，以评估阿尔茨海默病相关的神经病理学和细胞死亡成功减少转基因小鼠的淀粉样蛋白负荷、细胞死亡和记忆障碍可能为阿尔茨海默病的新治疗策略提供见解-治疗可以减少或预防阿尔茨海默病患者的神经变性和痴呆。