Age is one of the strongest risk factors for the development of neurodegenerative diseases, the majority of which involve misfolded protein aggregates in the brain. These protein aggregates are thought to drive pathology and are attractive targets for the development of new therapies. However, it is unclear how age influences the onset of pathology and the accompanying molecular response. To address this knowledge gap, we used a model of seeded tau pathology to profile the transcriptomic changes in 3 and 12 month old mice in response to developing tau hyperphosphorylation and aggregation. First, we found the burden of hyperphosphorylated tau pathology in mice injected at 12 months of age was moderately reduced compared to animals injected at 3 months. On a molecular level, we found an inflammation-related subset of genes, including C3 and the disease-associated microglia genes Ctsd, Cst7, and Clec7a, were more expressed early in disease in 12 but not 3 month old mice. These findings provide evidence of an early, age-specific response to tau pathology, which could serve as a marker for the severity of downstream pathology.

中文翻译：

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对 tau 病理学的早期促炎转录反应具有年龄特异性，预示着 tau 负担的减少

年龄是神经退行性疾病发展的最强风险因素之一，其中大多数涉及大脑中错误折叠的蛋白质聚集体。这些蛋白质聚集体被认为会驱动病理学，并且是开发新疗法的有吸引力的目标。然而，尚不清楚年龄如何影响病理的发作和伴随的分子反应。为了解决这一知识差距，我们使用种子 tau 病理学模型来分析 3 个月和 12 个月大的小鼠对发展 tau 过度磷酸化和聚集的反应的转录组变化。首先，我们发现与 3 个月时注射的动物相比，在 12 个月大时注射的小鼠中过度磷酸化 tau 病理学的负担适度减少。在分子水平上，我们发现了一个与炎症相关的基因子集，包括C3和与疾病相关的小胶质细胞基因Ctsd、Cst7和Clec7a在 12 个月大但不是 3 个月大的小鼠中在疾病早期表达更多。这些发现提供了对 tau 病理的早期、年龄特异性反应的证据，这可以作为下游病理严重程度的标志。