Alzheimer’s-linked axonal changes accompany elevated antidromic action potential failure rate in aged mice

• Published in: Brain research 2024-10, Vol.1841, p.149083, Article 149083
• Main Authors: Russo, Matthew L., Ayala, Gelique, Neal, Demetria, Rogalsky, Annalise E., Ahmad, Suzan, Musial, Timothy F., Pearlman, Morgan, Bean, Linda A., Farooqi, Anise K., Ahmed, Aysha, Castaneda, Adrian, Patel, Aneri, Parduhn, Zachary, Haddad, Loreece G., Gabriel, Ashley, Disterhoft, John F., Nicholson, Daniel A.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Antidromic action potentials; CA1; Myelin; Sodium channel; White matter
• ISSN: 0006-8993; 1872-6240; 1872-6240
• DOI: 10.1016/j.brainres.2024.149083

[Display omitted] •Ultrastructure of myelin is disrupted in human AD hippocampal white matter.•Myelin ultrastructure is disrupted in hippocampal white matter of aged ADTg mice.•Antidromic action potential propagation is less reliable in aged ADTg mice.•NaV1.6 levels are elevated at the nodes of Ranvier in aged ADTg mice.•NaV1.6 is sequestered in dystrophic neurites in ADTg mice. Alzheimer’s disease (AD) affects both grey and white matter (WM), but considerably more is known about the former. Interestingly, WM disruption has been consistently observed and thoroughly described using imaging modalities, particularly MRI which has shown WM functional disconnections between the hippocampus and other brain regions during AD pathogenesis when early neurodegeneration and synapse loss are also evident. Nonetheless, high-resolution structural and functional analyses of WM during AD pathogenesis remain scarce. Given the importance of the myelinated axons in the WM for conveying information across brain regions, such studies will provide valuable information on the cellular drivers and consequences of WM disruption that contribute to the characteristic cognitive decline of AD. Here, we employed a multi-scale approach to investigate hippocampal WM disruption during AD pathogenesis and determine whether hippocampal WM changes accompany the well-documented grey matter losses. Our data indicate that ultrastructural myelin disruption is elevated in the alveus in human AD cases and increases with age in 5xFAD mice. Unreliable action potential propagation and changes to sodium channel expression at the node of Ranvier co-emerged with this deterioration. These findings provide important insight to the neurobiological substrates and functional consequences of decreased WM integrity and are consistent with the notion that hippocampal disconnection contributes to cognitive changes in AD.