School of Medicine, Western Sydney University, Penrith, NSW, 2751, Australia.
School of Science, Western Sydney University, Penrith, NSW, 2751, Australia.
J Neuroinflammation. 2023 Oct 13;20(1):235. doi: 10.1186/s12974-023-02897-5.
Low-grade, chronic inflammation in the central nervous system characterized by glial reactivity is one of the major hallmarks for aging-related neurodegenerative diseases like Alzheimer's disease (AD). The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex and may be differentially vulnerable in various neurodegenerative diseases. However, the impact of chronic neuroinflammation on the cholinergic function is still unclear.
To gain further insight into age-related cholinergic decline, we investigated the cumulative effects of aging and chronic neuroinflammation on the structure and function of the septal cholinergic neurons in transgenic mice expressing interleukin-6 under the GFAP promoter (GFAP-IL6), which maintains a constant level of gliosis. Immunohistochemistry combined with unbiased stereology, single cell 3D morphology analysis and in vitro whole cell patch-clamp measurements were used to validate the structural and functional changes of BFCN and their microglial environment in the medial septum.
Stereological estimation of MS microglia number displayed significant increase across all three age groups, while a significant decrease in cholinergic cell number in the adult and aged groups in GFAP-IL6 mice compared to control. Moreover, we observed age-dependent alterations in the electrophysiological properties of cholinergic neurons and an increased excitability profile in the adult GFAP-IL6 group due to chronic neuroinflammation. These results complimented the significant decrease in hippocampal pyramidal spine density seen with aging and neuroinflammation.
We provide evidence of the significant impact of both aging and chronic glial activation on the cholinergic and microglial numbers and morphology in the MS, and alterations in the passive and active electrophysiological membrane properties of septal cholinergic neurons, resulting in cholinergic dysfunction, as seen in AD. Our results indicate that aging combined with gliosis is sufficient to cause cholinergic disruptions in the brain, as seen in dementias.
中枢神经系统的低度、慢性炎症以胶质反应为特征，是阿尔茨海默病（AD）等与衰老相关的神经退行性疾病的主要标志之一。基底前脑胆碱能神经元（BFCN）为人类大脑皮层提供胆碱能支配的主要来源，并且在各种神经退行性疾病中可能具有不同的易感性。然而，慢性神经炎症对胆碱能功能的影响仍不清楚。
为了更深入地了解与年龄相关的胆碱能下降，我们研究了在表达白细胞介素 6 的转基因小鼠中，年龄和慢性神经炎症对隔区胆碱能神经元结构和功能的累积影响，该基因在 GFAP 启动子（GFAP-IL6）下表达，可维持持续的神经胶质增生水平。免疫组织化学结合无偏立体学、单细胞 3D 形态分析和体外全细胞膜片钳测量用于验证内侧隔核 BFCN 及其小胶质细胞环境的结构和功能变化。
立体学估计 MS 小胶质细胞数量在所有三个年龄组中均显著增加，而在成年和老年 GFAP-IL6 组中，与对照组相比，胆碱能细胞数量显著减少。此外，我们观察到成年 GFAP-IL6 组的胆碱能神经元的电生理特性随年龄发生变化，并且由于慢性神经炎症而导致兴奋性增加。这些结果补充了由于衰老和神经炎症而导致海马锥体神经元密度显著减少的结果。
我们提供了证据表明，年龄和慢性胶质激活对 MS 中的胆碱能和小胶质细胞数量和形态以及隔区胆碱能神经元的被动和主动电生理膜特性的改变均有显著影响，导致胆碱能功能障碍，如在 AD 中所见。我们的结果表明，衰老与神经胶质增生相结合足以导致大脑中的胆碱能紊乱，如在痴呆症中所见。
