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Updated: Jun 24, 2025
Preparation of Acute Hippocampal Slices from Rats and Transgenic Mice for the Study of Synaptic Alterations during Aging and Amyloid Pathology
Published on: March 23, 2011
Alzheimer's-linked axonal changes accompany elevated antidromic action potential failure rate in aged mice
Matthew L Russo1, Gelique Ayala1, Demetria Neal1
1Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Abstract:
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.
Insights
Alzheimer's disease causes white matter (WM) damage in the hippocampus, affecting nerve signal transmission. This study reveals myelin breakdown and altered sodium channels in WM, contributing to cognitive decline in Alzheimer's disease (AD).
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.
