Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
Mol Neurobiol. 2019 Jul;56(7):5095-5110. doi: 10.1007/s12035-018-1427-8. Epub 2018 Nov 27.
Kainic acid (KA) is an analogue of the excitatory neurotransmitter glutamate that, when injected systemically into adult rats, can trigger seizures and progressive neuronal loss in a manner that mirrors the neuropathology of human mesial temporal lobe epilepsy. However, biomolecular mechanisms responsible for the neuronal loss that occurs as a consequence of this treatment remains elusive. We have recently reported that toxicity induced by KA can partly be mediated by astrocyte-derived amyloid β (Aβ) peptides, which are critical in the development of Alzheimer's disease (AD). Nonetheless, little is known how KA can influence amyloid precursor protein (APP) levels and processing in astrocytes. Thus, in the present study using human U-373 astrocytoma and rat primary astrocytes, we evaluated the role of KA on APP metabolism. Our results revealed that KA treatment increased the levels of APP and its cleaved products (α-/β-CTFs) in cultured U-373 astrocytoma and primary astrocytes, without altering the cell viability. The cellular and secretory levels of Aβ/Aβ were markedly increased in KA-treated astrocytes. We also demonstrated that the steady-state levels of APP-secretases were not altered but the activity of γ-secretase is enhanced in KA-treated U-373 astrocytoma. Furthermore, using selective receptor antagonists, we showed that the effects of KA is mediated by activation of kainate receptors and not NMDA or AMPA receptors. These results suggest that KA can enhance amyloidogenic processing of APP by activating its own receptor leading to increased production/secretion of Aβ-related peptides from activated astrocytes which may contribute to the pathogenesis of temporal lobe epilepsy.
海人酸（KA）是一种与兴奋性神经递质谷氨酸类似的物质，当它被系统性地注射到成年大鼠体内时，可以引发癫痫发作，并以类似于人类内侧颞叶癫痫的神经病理学方式导致进行性神经元丧失。然而，导致这种治疗后神经元丧失的生物分子机制仍不清楚。我们最近报道称，KA 诱导的毒性部分可以由星形胶质细胞衍生的淀粉样β（Aβ）肽介导，这些肽在阿尔茨海默病（AD）的发展中至关重要。尽管如此，人们对 KA 如何影响星形胶质细胞中的 APP 水平和加工过程知之甚少。因此，在本研究中，我们使用人 U-373 星形细胞瘤和大鼠原代星形胶质细胞，评估了 KA 对 APP 代谢的影响。我们的结果表明，KA 处理增加了培养的 U-373 星形细胞瘤和原代星形胶质细胞中 APP 及其裂解产物（α-/β-CTFs）的水平，而不改变细胞活力。KA 处理的星形胶质细胞中 Aβ/Aβ 的细胞和分泌水平明显增加。我们还证明，KA 处理不会改变 APP 分泌酶的稳态水平，但会增强 U-373 星形胶质细胞中 γ-分泌酶的活性。此外，使用选择性受体拮抗剂，我们表明 KA 的作用是通过激活 kainate 受体介导的，而不是 NMDA 或 AMPA 受体。这些结果表明，KA 可以通过激活其自身受体增强 APP 的淀粉样生成加工，从而增加激活的星形胶质细胞中 Aβ 相关肽的产生/分泌，这可能有助于颞叶癫痫的发病机制。
