Chronic sialidase effects on amyloid aggregation and associated pathology

阿尔茨海默病的特点是β-淀粉样蛋白(A-β)在大脑中聚集，分布广泛 神经退化和认知能力下降。我们的工作重点是通过以下方式改善阿尔茨海默氏症的病理 减少或简化主要的脑神经节苷脂和促细胞凋亡的神经节苷脂GD3。神经节苷脂 神经鞘糖脂在脑组织中大量表达。我们之前已经证明，击倒 编码GD3S(St8sia1)的基因显著减少Aβ聚集和氧化应激，并防止 携带突变型人淀粉样前体蛋白转基因小鼠的记忆缺陷 早老素1(PSEN1)，已知导致阿尔茨海默病的基因。此外，GD3S的原代神经元 基因敲除小鼠对Aβ诱导的细胞死亡具有抵抗力。然而，这些小鼠出生时就没有GD3S，而且 它们缺乏许多对正常大脑发育至关重要的神经节苷脂。建议的目标是 研究旨在确定b系列神经节苷脂和GD1a在体内的降解是否与 敲除GD3S基因对5xFAD阿尔茨海默病模型小鼠阿尔茨海默病的缓解作用 疾病。拟议研究的一般假设是霍乱弧菌唾液酸酶(VCS)将 成功减少斑块形成，阻止细胞死亡，并防止成年突变体的记忆障碍 老鼠。在拟议的实验中，将长期实施VCS，以评估5xFAD的疗效 转基因小鼠。将对所有小鼠的认知、焦虑和感觉运动功能进行评估。验尸报告 分析将包括评估阿尔茨海默病相关神经病理和细胞的完整分析 死亡。成功降低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洞察-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症。

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.