Shenzhen Bay Laboratory, Institute of Biomedical Engineering, Shenzhen, China.
Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.
Ann Neurol. 2024 May;95(5):917-928. doi: 10.1002/ana.26885. Epub 2024 Feb 14.
Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable.
We identified 663 participants with baseline β-amyloid (Aβ) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p-Tau), soluble TREM2 (sTREM2), PGRN, and growth-associated protein-43 (GAP-43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aβ PET, CSF p-Tau, and CSF GAP-43 cross-sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation.
Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p-Tau was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aβ burden was associated with attenuated CSF p-Tau effects on CSF microglial biomarker increases. Independent of Aβ PET and CSF p-Tau pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP-43 levels and faster rates of CSF GAP-43 increase.
These findings suggest that higher Aβ burden may attenuate the p-Tau-associated microglial responses, and TREM2-related microglial reactivity may independently correlate with GAP-43-related presynaptic loss. This study highlights the two-edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917-928.
髓样细胞触发受体-2（TREM2）和颗粒体蛋白前体（PGRN）是小胶质细胞激活的关键调节因子，可在脑脊液（CSF）中检测到。然而，小胶质细胞的反应性对阿尔茨海默病（AD）是有害的还是神经保护性的，仍存在争议。
我们确定了 663 名基线时β-淀粉样蛋白（Aβ）正电子发射断层扫描（PET）和 CSF 生物标志物数据的参与者，包括磷酸化 tau181（p-Tau）、可溶性 TREM2（sTREM2）、PGRN 和生长相关蛋白-43（GAP-43）。其中，254 名参与者有同时的纵向 CSF 生物标志物数据。我们使用多元回归分析研究了 CSF 小胶质细胞生物标志物与 Aβ PET、CSF p-Tau 和 CSF GAP-43 的横断面和纵向相关性。一个中国老龄化队列的独立 CSF 样本（n=65）也进行了分析作为验证。
较高的基线 CSF 小胶质细胞生物标志物水平与 CSF sTREM2 增加和 CSF PGRN 减少的更快速度相关。较高的 CSF p-Tau 与较高的 CSF 小胶质细胞生物标志物水平和 CSF sTREM2 增加以及 CSF PGRN 减少的更快速度相关。在两个队列中，较高的 Aβ 负担与减弱 CSF p-Tau 对 CSF 小胶质细胞生物标志物增加的影响有关。独立于 Aβ PET 和 CSF p-Tau 病理，较高的 CSF sTREM2 水平但不是 CSF PGRN 水平与 CSF GAP-43 水平升高和 CSF GAP-43 增加的更快速度相关。
这些发现表明，较高的 Aβ 负担可能会减弱 p-Tau 相关的小胶质细胞反应，而与 TREM2 相关的小胶质细胞反应可能与与 GAP-43 相关的突触前丢失独立相关。本研究强调了小胶质细胞反应在 AD 和其他神经退行性疾病中的双刃剑作用。
