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

Area of Science:

• Neuroscience
• Neuropathology
• Biomedical Imaging

Background:

• Alzheimer's disease (AD) impacts both grey and white matter (WM), with significant grey matter (GM) changes well-documented.
• White matter (WM) disruption, particularly hippocampal disconnections, is observed in AD, correlating with neurodegeneration and synapse loss.
• High-resolution studies on WM alterations during AD pathogenesis are limited, despite the critical role of myelinated axons in brain communication.

Purpose of the Study:

• To investigate hippocampal WM disruption during AD pathogenesis using a multi-scale approach.
• To determine if hippocampal WM changes correlate with documented grey matter losses in Alzheimer's disease.
• To elucidate the cellular drivers and functional consequences of WM disruption contributing to cognitive decline in AD.

Main Methods:

• Multi-scale analysis of hippocampal white matter (WM) in human Alzheimer's disease (AD) cases and 5xFAD mouse models.
• Ultrastructural examination of myelin integrity within the alveus.
• Assessment of action potential propagation and sodium channel expression at the node of Ranvier.

Main Results:

• Elevated ultrastructural myelin disruption was observed in the alveus of human AD cases.
• Myelin deterioration in the hippocampus increased with age in 5xFAD mice.
• Impaired action potential propagation and altered sodium channel expression at the node of Ranvier were associated with myelin damage.

Conclusions:

• Ultrastructural myelin damage in the hippocampus is a significant feature of Alzheimer's disease (AD) pathogenesis.
• These WM changes, including impaired nerve impulse conduction, contribute to the neurobiological basis of cognitive decline in AD.
• Hippocampal WM integrity is crucial, and its disruption, alongside GM loss, likely drives cognitive impairment in Alzheimer's disease.