Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Graduate Program in Biological Sciences-Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Nat Med. 2023 Jul;29(7):1775-1781. doi: 10.1038/s41591-023-02380-x. Epub 2023 May 29.
An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.
阿尔茨海默病（AD）病理生理学的一个未解决的问题是，为什么大量淀粉样蛋白-β（Aβ）阳性认知正常（CU）个体不会发展为可检测的下游tau 病理学，从而不会出现临床恶化。体外证据表明，反应性星形胶质细胞释放 Aβ 对病理性 tau 磷酸化的影响。在这里，在三个队列（n=1016）的生物标志物研究中，我们测试了星形胶质细胞反应是否调节 CU 个体中 Aβ 与 tau 磷酸化的关联。我们发现，只有在星形胶质细胞反应阳性（Ast）的个体中，Aβ 才与血浆中磷酸化 tau 的增加相关。横断面和纵向 tau 正电子发射断层扫描分析显示，只有在 CU Ast 个体中，tau 缠结的积累呈现出 AD 样模式，这与 Aβ 有关。我们的研究结果表明，星形胶质细胞反应是将 Aβ 与初始 tau 病理学联系起来的一个重要上游事件，这可能对临床前 AD 的生物学定义以及为临床试验选择 CU 个体具有重要意义。
