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Alzheimer's Disease, Other Dementia, Aging

開催日 2014/9/11
時間 16:00 - 17:00
会場 Poster / Exhibition(Event Hall B)

Increased synaptic density and improved spatial memory in N-cadherin shedding deficient knock-in mice

  • P1-292
  • 浅田 めぐみ / Megumi Asada:1,2 久保田 正和 / Masakazu Kubota:1 野田 秦葉 / Yasuha Noda:1 上田 奈津実 / Natumi Ageta:4 諏訪 あゆみ / Ayumi Suwa:1 宮本 将和 / Masakazu Miyamoto:2 田代 喜崇 / Yoshitaka Tashiro:5 山門 穂高 / Hodaka Yamakado:2 山下 博史 / Hirofumi Yamashita:2 下濱 俊 / Shun Shimohama:3 高橋 良輔 / Ryoshuke Takahashi:2 植村 健吾 / Kengo Uemura:2 木下 専 / Makoto Kinoshita:4 木下 彩栄 / Ayae Kinoshita:1 
  • 1:京都大院医人間健康 / Dept Med,Human Health Sci.Grad.Sch.Kyoto Univ.Kyoto, Japan 2:京都大医学部付属病院神経内科 / Dept.Neuro.kyoto Univ.Grad.Sch.Med. Kyoto, Japan 3:札幌医大神経内科 / Dept. Neuro. Sappro Med. Univ. Sapporo, Japan 4:名大・院・理・生命理学 / Division of Biological Science,Graduate School of Science,Nagoya University, Nagoya Japan 5:京大・院・医・MIC・SKプロジェクト / SK project ・ MIC Kyoto Univ. Grad. Sch. Med 

Alzheimer's disease (AD) is the most prevalent cause of dementia. In AD, synaptic loss is one of the principal pathological hallmarks, and correlates with the severity of cognitive impairment. N-cadherin is a representative cell adhesion molecule, which plays an important role in synapse formation, especially in hippocampal excitatory neurons. N-cadherin not only maintains synaptic structure, but also actively regulates synaptic plasticity. N-cadherin undergoes sequential cleavage by ADAM10 and PS1, however, the significance of the cleavage has not been clarified. To investigate for the significance of N-cadherin cleavage in vivo, we analyzed ADAM10-mediated cleavage-defective (i.e. ectodomain shedding deficient) N-cadherin knock-in (KI) mice.
As expected, the cleavage of N-cadherin by ADAM10 was not observed in the brain or primary neuron obtained from the KI mice.
KI mice were viable and retained normal reproduction capacity, but demonstrated weight loss. Electronmicroscopic analysis of hippocampal CA3 region showed significant decrease of PSD area in KI mice as compared to WT mice but showed no difference in spine volume.
Interestingly, physical dissector method showed increased synaptic density in KI mice. Accordingly, KI mice showed significantly better performance in the radial maze test compared to WT mice.
Thus, our results suggested that the inhibition of N-cadherin cleavage by ADAM10 might lead to stabilization of synapses, leading to better working memory.

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