Pascoal Tharick, Rohden Francieli, Ferreira Pamela, Bellaver Bruna, Ferrari-Souza João Pedro, Aguzzoli Cristiano, Soares Carolina, Abbas Sarah, Zalzale Hussein, Povala Guilherme, Lussier Firoza, Leffa Douglas, Bauer-Negrini Guilherme, Rahmouni Nesrine, Tissot Cécile, Therriault Joseph Therriault, Servaes Stijn, Stevenson Jenna, Benedet Andrea, Ashton Nicholas, Karikari Thomas, Tudorascu Dana, Zetterberg Henrik, Blennow Kaj, Zimmer Eduardo, Souza Diogo, Rosa-Neto Pedro
Res Sq. 2024 Aug 12:rs.3.rs-4782732. doi: 10.21203/rs.3.rs-4782732/v1.
Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease(AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available CSF measures of amyloid-β(Aβ), phosphorylated tau(pTau181), astrocyte reactivity(GFAP), microglial activation(sTREM2), and synaptic biomarkers(GAP43 and neurogranin). Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aβ presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aβ + individuals and postsynaptic biomarkers in cognitively impaired Aβ + individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.
先前的研究表明，神经胶质和神经元的变化可能会引发阿尔茨海默病（AD）中的突触功能障碍。然而，神经胶质和神经元标志物与活体大脑中突触异常之间的联系却鲜为人知。在此，我们研究了来自两个队列的478名处于衰老和AD谱系中的个体中，星形胶质细胞和小胶质细胞反应性的生物标志物与突触功能障碍之间的关联，这些个体可获得脑脊液中淀粉样蛋白-β（Aβ）、磷酸化tau蛋白（pTau181）、星形胶质细胞反应性（GFAP）、小胶质细胞激活（sTREM2）以及突触生物标志物（GAP43和神经颗粒素）的检测结果。脑脊液GFAP水平升高与突触前和突触后功能障碍相关，无论认知状态或Aβ是否存在。脑脊液sTREM2水平与认知未受损和Aβ阳性且认知受损个体的突触前生物标志物以及Aβ阳性且认知受损个体的突触后生物标志物相关。值得注意的是，脑脊液pTau181水平介导了GFAP或sTREM2水平与突触功能障碍生物标志物之间的所有关联。这些结果表明，与神经元相关的突触生物标志物可用于针对AD中神经胶质反应性的临床试验。
