Zheng Xiang-Yu, Zhang Hai-Chen, Lv Yu-Dan, Jin Feng-Yan, Wu Xiu-Juan, Zhu Jie, Ruan Yang
Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
Department of Hematology, Cancer Center, The First Hospital of Jilin University, Changchun, China.
Front Aging Neurosci. 2022 Aug 25;14:888784. doi: 10.3389/fnagi.2022.888784. eCollection 2022.
Patients with Alzheimer's disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)-a drug for treating seizures-on learning and memory and the neuropathological features of AD.
We crossbred APP23 mice with microtubule-associated protein tau (MAPT) transgenic mice to generate APP23/MAPT mice. These mice were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months.
Low doses of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/β, thus rescuing neurons from synaptic dystrophy and apoptosis. Low doses of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid β-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid β-peptide (Aβ) by reducing the expression of β-site APP-cleaving enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement ability in mice, and did not alleviate cognitive decline in AD mice.
Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. A low concentration of LEV may help ameliorate abnormalities of AD; however, a high LEV concentration did not induce similar results.
与年龄匹配的其他个体相比，阿尔茨海默病（AD）患者发生癫痫的风险显著更高，这表明癫痫与AD之间存在密切关联。我们旨在研究用于治疗癫痫的药物左乙拉西坦（LEV）对学习记忆以及AD神经病理学特征的影响。
我们将APP23小鼠与微管相关蛋白tau（MAPT）转基因小鼠杂交，以生成APP23/MAPT小鼠。在存在 kainic 酸（KA）的情况下，用不同浓度的LEV对这些小鼠进行3个月的治疗。
低剂量的LEV减轻了KA对APP23/MAPT小鼠记忆缺陷的影响。机制研究表明，低浓度的LEV通过降低细胞周期蛋白依赖性激酶5和糖原合酶激酶3α/β的活性来减少tau磷酸化，从而使神经元免受突触营养不良和凋亡的影响。低剂量的LEV抑制了KA的作用（即诱导神经炎症和损害淀粉样β肽的自噬），从而改善认知功能下降。高浓度的LEV通过降低β位点APP裂解酶1和早老素1的表达来减少淀粉样β肽（Aβ）的产生和沉积。然而，高浓度的LEV也诱导神经元凋亡，降低小鼠的运动能力，并且并未减轻AD小鼠的认知功能下降。
我们的结果支持异常网络活动导致APP23/MAPT小鼠突触和认知缺陷的假说。低浓度的LEV可能有助于改善AD的异常情况；然而，高浓度的LEV并未产生类似的结果。
