Neuroprotective effect of memantine on the retinal ganglion cells of APPswe/PS1ΔE9 mice and its immunomodulatory mechanisms.
Besides the cognitive impairment and degeneration in the brain, vision dysfunction and retina damage are always prevalent in patients with Alzheimer's disease (AD). The uncompetitive antagonist of the N-methyl-d-aspartate receptor, memantine (MEM), has been proven to improve the cognition of patients with AD. However, limited information exists regarding the mechanism of neurodegeneration and the possible neuroprotective mechanisms of MEM on the retinas of patients with AD. In the present study, by using APPswe/PS1ΔE9 double transgenic (dtg) mice, we found that MEM rescued the loss of retinal ganglion cells (RGCs), as well as improved visual impairments, including improving the P50 component in pattern electroretinograms and the latency delay of the P2 component in flash visual evoked potentials of APPswe/PS1ΔE9 dtg mice. The activated microglia in the retinas of APPswe/PS1ΔE9 dtg mice were also inhibited by MEM. Additionally, the level of glutamine synthetase expressed by Müller cells within the RGC layer was upregulated in APPswe/PS1ΔE9 dtg mice, which was inhibited by MEM. Simultaneously, MEM also reduced the apoptosis of choline acetyl transferase-immunoreactive cholinergic amacrine cells within the RGC layer of AD mice. Moreover, the phosphorylation level of extracellular regulated protein kinases 1 and 2 was increased in APPswe/PS1ΔE9 dtg mice, which was blocked by MEM treatment. These findings suggest that MEM protects RGCs in the retinas of APPswe/PS1ΔE9 dtg mice by modulating the immune response of microglia and the adapted response of Müller cells, making MEM a potential ophthalmic treatment alternative in patients with AD.
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China; Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing 400038, China. Electronic address: glx919@163.com.
Lixiong
L
Gao
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China; School of Medicine, Nankai University, Tianjin 300071, China; Department of Ophthalmology, Chinese People's Liberation Army General Hospital, Beijing 100853, China. Electronic address: tencycx@hotmail.com.
Xi
X
Chen
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: typ126@126.com.
Yongping
Y
Tang
Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing 400038, China. Electronic address: zhaojinghui110@163.com.
Jinghui
J
Zhao
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: lqy111lcy@126.com.
Qiyou
Q
Li
Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing 400038, China. Electronic address: fanxiaotang2005@163.com.
Xiaotang
X
Fan
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: haiweixu2001@163.com.
Haiwei
H
Xu
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: qinzyin@aliyun.com.
Zheng Qin
ZQ
Yin
D000544:Alzheimer Disease / Q000188:drug therapy; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography / Q000187:drug effects; D063928:Ependymoglial Cells / Q000187:drug effects; D005074:Evoked Potentials, Visual / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009410:Nerve Degeneration / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*
D018696:Neuroprotective Agents; D005974:Glutamate-Ammonia Ligase; D008559:Memantine
Alzheimer's disease; Memantine; Microglia; Müller cell; Retinal ganglion cell