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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)

Inhibition of clathrin-mediated endocytosis prevents amyloid β-induced growth cone collapse, axonal atrophy and memory impairment

  • P1-288
  • 久保山 友晴 / Tomoharu Kuboyama:1 李 英娥 / Young-A Lee:1 西子 裕章 / Hiroaki Nishiko:1 東田 千尋 / Chihiro Tohda:1 
  • 1:富山大・和漢研・神経機能 / Div of Neuromedical Sci, Inst of Natural Med, Univ of Toyama 

In Alzheimer's disease (AD), amyloid β (Aβ)-induced axonal atrophy is a major cause of AD pathology. However, the critical target to prevent Aβ-induced axonal atrophy remains unknown. Here, we analysed growth cone collapse elicited by Aβ, a putative early Aβ-induced event in axons. Although no study has yet shown influence of Aβ on the growth cone, we first visualized growth cone collapse at 1 h after the Aβ-treatment in cultured neurons. Pharmacological analysis indicated that Aβ induces Ca2+ influx, possibly via NMDA receptor and TRP channel, activates calpain and calcineurin and then facilitates clathrin-mediated endocytosis. Furthermore, Aβ-elicited endocytosis of FM1-43 was blocked by inhibitors relating to the above signal pathway. Next, inhibitors of clathrin-mediated endocytosis, myristoylated dynamin inhibitory peptide and pitstop 2, were intracerebroventricularly treated to mice before intracerebroventricular injection of Aβ. The injection of Aβ induced axonal atrophy in the cerebral cortex and hippocampus, and impaired object recognition, objet location and episodic memories. Treatment with the endocytosis inhibitors prevented axonal atrophy and memory impairment in the Aβ-injected mice. Our results clarified the important role of clathrin-mediated endocytosis in Aβ-induced collapse of growth cone that may lead to axonal atrophy and memory loss.

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