Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 40530 Gothenburg, Sweden.
J Neuroinflammation. 2023 Nov 24;20(1):278. doi: 10.1186/s12974-023-02962-z.
Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears.
We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages.
14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss.
Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.
在阿尔茨海默病（AD）的后期阶段，突触丢失与tau 聚集和小胶质细胞激活密切相关。然而，在 AD 的早期阶段，tau 积累的早期就已经发生了突触损伤。目前尚不清楚小胶质细胞激活是否会在 tau 聚集出现之前独立导致突触断裂。
我们通过测量脑脊液中突触降解的生物标志物 14-3-3 zeta/delta ([Formula: see text])，以及 tau、淀粉样蛋白、星形胶质细胞增生、神经退行性变和炎症的液体和成像生物标志物，研究了跨越 AD 连续体的 104 名参与者。我们在认知正常和受损的参与者中进行了相关分析，并使用结构方程模型来估计小胶质细胞激活对不同疾病阶段突触损伤的影响。
在 tau 聚集的早期阶段，在海马体积损失可检测之前，淀粉样蛋白病理患者的 14-3-3 [Formula: see text] 增加。在所有参与者中，14-3-3 [Formula: see text] 与淀粉样蛋白和 tau 负荷相关，但仅与认知正常参与者的神经退行性变和记忆缺陷的生物标志物相关。这种早期的突触损伤是由 sTREM2 独立介导的。在疾病的后期阶段，tau 和星形胶质细胞增生进一步介导了突触丢失。
我们的研究结果表明，sTREM2 在 tau 积累的早期阶段介导了突触损伤，强调了小胶质细胞激活对 AD 疾病传播的重要性。
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