CHANGES IN WHITE MATTER MYELIN INTEGRITY DURING AD PATHOGENESIS

Abstract

Alzheimer's disease (AD) is known to involve substantial synapse loss and cell death, especially during later stages. While these consistently observed changes occur in the grey matter (GM), diffusion-tensor imaging (DTI) studies have shown that AD patients also exhibit changes to the white matter (WM). However, little work has been done to understand the cellular basis of these observations. It has been posited that WM changes are merely caused by Wallerian degeneration, but more recent studies have not supported this conclusion. A likely alternative explanation is that WM changes are due to a decrease in myelin integrity driven by the processes governing AD pathogenesis. The present study employed a combination of whole-cell patch clamp physiology and electron microscopy (EM) to assess myelin integrity during AD pathogenesis. In whole-cell patch clamp experiments, antidromic action potentials (APs) were evoked in CA1 pyramidal neurons from wild-type and 5xFAD mice to determine their respective abilities to propagate APs, which is largely influenced by myelination. In addition, the ultrastructure of myelin, including myelin thickness and abnormal myelination, in post-mortem human tissue and AD mouse models was assessed via EM. Antidromic AP propagation appears to vary substantially more in 5xFAD mouse neurons relative to controls. Specifically, some 5xFAD neurons appear functionally similar to controls, while a subset exhibit substantial deficits in antidromic AP propagation. This implies that functional properties dependent on myelination are altered in the presence of AD pathology. Additionally, abnormal patterns of myelination occur at significantly higher rates in aged 5xFAD mice than controls. This also appears to be the case in humans, with post-mortem AD tissue showing a much higher incidence of ultrastructural myelin abnormalities than tissue from non-cognitively impaired controls. The current data appear to support the hypothesis that WM changes during AD pathogenesis are due to decreased myelin integrity. Moreover, these changes also appear to have functional consequences at the cellular level, which likely result in deficits in neuronal communication.