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Axon initial segment (AIS) maintains the orderly structure of the axon and is responsible for initiating action potentials (APs). To investigate the role of AIS in early stages of AD pathogenesis, we focused on alterations in the AIS of neurons from APP\/PS1 mouse models harboring familial AD mutations. AIS length and electrophysiological properties were assessed in neurons using immunostaining and patch\u2010clamp techniques. The expression and function of ankyrin G (AnkG) isoforms were evaluated by western blot and rescue experiments. We observed a significant shortening of AIS in APP\/PS1 mice, which correlated with impaired action potential propagation. Furthermore, a decrease in the 480\u00a0kDa isoform of AnkG was observed. Rescue of this isoform restored AIS plasticity and improved long\u2010term potentiation in APP\/PS1 neurons. Our study implicates AIS plasticity alterations and AnkG dysregulation as early events in AD. The restoration of AIS integrity by the 480\u00a0kDa AnkG isoform presents a potential therapeutic strategy for AD, underscoring the importance of targeting AIS stability in neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/mco2.768","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T05:55:33Z","timestamp":1728971733000},"source":"Crossref","is-referenced-by-count":6,"title":["Alterations in the axon initial segment plasticity is involved in early pathogenesis in Alzheimer's disease"],"prefix":"10.1002","volume":"5","author":[{"given":"Yu","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Membrane Biology School of Life Sciences Peking University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology School of Life Sciences Peking University  Beijing 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