宿主年龄对颅内 AAV9 TauP301L 诱导的 Tau 病的影响。
Influence of Host Age on Intracranial AAV9 TauP301L Induced Tauopathy.
机构信息
Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA.
School of Aging Studies, University of South Florida, Tampa, FL, USA.
出版信息
J Alzheimers Dis. 2023;93(1):365-378. doi: 10.3233/JAD-221276.
BACKGROUND
Advanced age is the greatest risk factor for the development of Alzheimer's disease (AD). This implies that some aspect of the aged milieu is possibly accelerating the development of AD related pathologies.
OBJECTIVE
We hypothesized that intracranially injected with AAV9 tauP301L may cause a greater degree of pathology in old versus young mice.
METHODS
Animals were injected with viral vectors overexpressing the mutant tauP301L or control protein (green fluorescent protein, GFP) into the brains of mature, middle-aged, and old C57BL/6Nia mice. The tauopathy phenotype was monitored four months after injection using behavioral, histological, and neurochemical measures.
RESULTS
Phosphorylated-tau immunostaining (AT8) or Gallyas staining of aggregated tau increased with age, but other measures of tau accumulation were not significantly affected. Overall, AAV-tau injected mice had impaired radial arm water maze performance, increased microglial activation, and showed evidence of hippocampal atrophy. Aging impaired open field and rotarod performance in both AAV-tau and control mice. The efficiency of viral transduction and gene expression were the same at all animal ages.
CONCLUSION
We conclude that tauP301L over expression results in a tauopathy phenotype with memory impairment and accumulation of aggregated tau. However, the effects of aging on this phenotype are modest and not detected by some markers of tau accumulation, similar to prior work on this topic. Thus, although age does influence the development of tauopathy, it is likely that other factors, such as ability to compensate for tau pathology, are more responsible for the increased risk of AD with advanced age.
背景
年龄增长是阿尔茨海默病（AD）发病的最大风险因素。这意味着衰老微环境的某些方面可能加速了 AD 相关病理的发展。
目的
我们假设向老年和年轻小鼠颅内注射 AAV9tauP301L 可能会导致更严重的病理变化。
方法
向成熟、中年和老年 C57BL/6Nia 小鼠脑内注射过表达突变型 tauP301L 或对照蛋白（绿色荧光蛋白，GFP）的病毒载体。在注射后四个月，使用行为、组织学和神经化学测量来监测 tau 病表型。
结果
磷酸化 tau 免疫染色（AT8）或聚集 tau 的 Gallyas 染色随着年龄的增长而增加，但其他 tau 积累的测量指标没有明显受到影响。总的来说，AAV-tau 注射小鼠的放射臂水迷宫表现受损，小胶质细胞激活增加，并且表现出海马萎缩的迹象。衰老在 AAV-tau 和对照小鼠中均损害了旷场和转棒实验的表现。病毒转导和基因表达的效率在所有动物年龄都相同。
结论
我们得出结论，tauP301L 过表达导致tau 病表型，表现为记忆障碍和聚集 tau 的积累。然而，衰老对这种表型的影响是适度的，并且某些 tau 积累的标志物无法检测到，这与之前关于该主题的工作相似。因此，尽管年龄确实会影响 tau 病的发展，但其他因素，例如补偿 tau 病理学的能力，可能更负责随着年龄增长 AD 风险的增加。
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