Inhibition of clathrin-mediated endocytosis prevents amyloid β-induced axonal damage.

Amyloid β (Aβ)-induced axonal degeneration is a major cause of Alzheimer's disease (AD) pathology. However, the critical target to prevent Aβ-induced axonal degeneration remains unknown. Here, we analyzed 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 Aβ-initiated growth cone collapse in cultured neurons. Furthermore, we determined that the collapse was triggered by clathrin-mediated endocytosis probably via Aβ-Ca(2+) signaling. The inhibition of clathrin-mediated endocytosis prevented Aβ-induced axonal loss both in vitro and in vivo and prevented memory impairment in an AD mouse model. Our results clarified the important role of clathrin-mediated endocytosis in Aβ-induced collapse of growth cone that leads to axonal degeneration and memory impairment.