Neuronal Oscillations Laboratory, Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164, Solna, Sweden.
Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, BMC B11, 221 84, Lund, Sweden.
Transl Neurodegener. 2023 Feb 6;12(1):6. doi: 10.1186/s40035-023-00338-0.
Alzheimer's disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin-3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.
Here, we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo (20-80 Hz) by performing electrophysiological recordings in the hippocampal CA3 area of wild-type (WT) mice and of the 5×FAD mouse model of AD. In addition, the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes, and amyloid-β (Aβ) plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout (KO).
Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner, which was accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSNs) and pyramidal cells. We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevented Aβ42-induced degradation of gamma oscillations. Furthermore, the 5×FAD mice lacking gal3 (5×FAD-Gal3KO) exhibited WT-like gamma network dynamics and decreased Aβ plaque load.
We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs, inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.
阿尔茨海默病（AD）是一种进行性的多方面神经退行性疾病，目前尚无针对这种疾病的治疗方法。神经炎症是疾病进展的核心，有证据表明，小胶质细胞释放的半乳糖凝集素-3（gal3）通过放大 AD 中的神经炎症发挥关键作用。然而，gal3 是否参与破坏 AD 典型的神经元网络振荡仍不清楚。
在这里，我们通过在野生型（WT）小鼠和 AD 的 5×FAD 小鼠模型的海马 CA3 区进行电生理记录，研究了 gal3 信号对实验诱导的 gamma 振荡（20-80 Hz）的功能影响。此外，在急性 gal3 应用下，对 WT 小鼠的记录切片进行 RT-qPCR 分析，以检测一些神经炎症相关基因的表达，并用免疫染色法在 6 月龄的 5×FAD 小鼠的 CA3 区定量 Aβ 斑块负荷，这些小鼠存在或不存在 Gal3 敲除（KO）。
gal3 的应用以活动依赖性的方式降低了 gamma 振荡的功率和节律性，同时也损害了快发棘状神经元（FSNs）和锥体细胞的细胞动力学。我们发现，gal3 诱导的破坏是由 gal3 糖识别域介导的，并被 gal3 抑制剂 TD139 所阻止，后者也防止了 Aβ42 诱导的 gamma 振荡降解。此外，缺乏 gal3 的 5×FAD 小鼠（5×FAD-Gal3KO）表现出 WT 样的 gamma 网络动力学和减少的 Aβ 斑块负荷。
我们首次报告 gal3 通过 FSN 的尖峰相位解耦来破坏神经元网络动力学，导致网络性能崩溃。此外，我们的研究结果表明，gal3 抑制可能是一种潜在的治疗策略，以对抗 AD 及其他包含神经炎症和认知能力下降的神经退行性疾病的神经元网络不稳定。
