Levetiracetam alleviates cognitive decline in Alzheimer's disease animal model by ameliorating the dysfunction of the neuronal network

被引：14
作者：
Zheng, Xiang-Yu [1 ,2 ]
Zhang, Hai-Chen [1 ,2 ]
Lv, Yu-Dan [1 ,2 ]
Jin, Feng-Yan [3 ]
Wu, Xiu-Juan [1 ,2 ]
Zhu, Jie [1 ,2 ,4 ]
Ruan, Yang [5 ]
机构：
[1] First Hosp Jilin Univ, Dept Neurol, Changchun, Peoples R China
[2] First Hosp Jilin Univ, Ctr Neurosci, Changchun, Peoples R China
[3] First Hosp Jilin Univ, Ctr Canc, Dept Hematol, Changchun, Peoples R China
[4] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden
[5] Jilin Univ, Coll Basic Med Sci, Key Lab Pathobiol, Minist Educ, Changchun, Peoples R China
来源：
FRONTIERS IN AGING NEUROSCIENCE | 2022年 / 14卷
基金：
中国国家自然科学基金;
关键词：
neuronal dystrophy; neuroinflammation; inflammasome; amyloid b-peptide; dementia; AMYLOID-BETA-PROTEIN; INFLAMMATORY CYTOKINES; BEHAVIORAL DEFICITS; MEMORY DEFICITS; TAU PATHOLOGY; MOUSE MODEL; IMPAIRMENTS; AUTOPHAGY; DEMENTIA; NEUROIMMUNOMODULATION;
D O I：
10.3389/fnagi.2022.888784
中图分类号：
R592 [老年病学]; C [社会科学总论];
学科分类号：
03 ; 0303 ; 100203 ;
摘要：
Background: 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. Methods: 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. Results: 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 3 a/ b, 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 b-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid b-peptide (Ab) by reducing the expression of b-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. Conclusion: 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.
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页数：14
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