TY - JOUR
T1 - Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice
AU - Zhang, Mao-Ying
AU - Zheng, Chuan-Yi
AU - Zou, Ming-Ming
AU - Zhu, Jian-Wei
AU - Zhang, Yan
AU - Wang, Jing
AU - Liu, Chun-Feng
AU - Li, Qi-Fa
AU - Xiao, Zhi-Cheng
AU - Li, Shao
AU - Ma, Quan-Hong
AU - Xu, Ru-Xiang
PY - 2014
Y1 - 2014
N2 - Hyperactivity and its compensatory mechanisms may causally contribute to synaptic and cognitive deficits in Alzheimer s disease (AD). Blocking the overexcitation of the neural network, with levetiracetam (LEV), a sodium channel blocker applied in the treatment of epilepsy, prevented synaptic and cognitive deficits in human amyloid precursor protein (APP) transgenic mice. This study has brought the potential use of antiepileptic drugs (AEDs) in AD therapy. We showed that the chronic treatment with lamotrigine (LTG), a broad-spectrum AED, suppressed abnormal spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (PS1) mice, which express human mutant APP and PS1. In contrast with LEV, which failed to reduce the generation of amyloid beta, the chronic LTG treatment reduced the cleavage of APP by beta-secretase and thus the numbers and the size of amyloid plaques in the brains of APP and PS1 mice. Moreover, the levels of brain-derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF) were enhanced in the brains of APP and PS1 mice by the chronic LTG treatment. Therefore, these observations demonstrate that LTG attenuates AD pathology through multiple mechanisms, including modulation of abnormal network activity, reduction of the generation of amyloid beta and upregulation of BDNF and NGF.
AB - Hyperactivity and its compensatory mechanisms may causally contribute to synaptic and cognitive deficits in Alzheimer s disease (AD). Blocking the overexcitation of the neural network, with levetiracetam (LEV), a sodium channel blocker applied in the treatment of epilepsy, prevented synaptic and cognitive deficits in human amyloid precursor protein (APP) transgenic mice. This study has brought the potential use of antiepileptic drugs (AEDs) in AD therapy. We showed that the chronic treatment with lamotrigine (LTG), a broad-spectrum AED, suppressed abnormal spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (PS1) mice, which express human mutant APP and PS1. In contrast with LEV, which failed to reduce the generation of amyloid beta, the chronic LTG treatment reduced the cleavage of APP by beta-secretase and thus the numbers and the size of amyloid plaques in the brains of APP and PS1 mice. Moreover, the levels of brain-derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF) were enhanced in the brains of APP and PS1 mice by the chronic LTG treatment. Therefore, these observations demonstrate that LTG attenuates AD pathology through multiple mechanisms, including modulation of abnormal network activity, reduction of the generation of amyloid beta and upregulation of BDNF and NGF.
UR - http://www.sciencedirect.com/science/article/pii/S019745801400428X
U2 - 10.1016/j.neurobiolaging.2014.06.009
DO - 10.1016/j.neurobiolaging.2014.06.009
M3 - Article
SN - 0197-4580
VL - 35
SP - 2713
EP - 2725
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 12
ER -