Accelerated Dystrophy and Decay of Oligodendrocyte Precursor Cells in the APP/PS1 Model of Alzheimer's-Like Pathology.

Irene Chacon-De-La-Rocha,Olivier Raineteau,Andrea D Rivera,Gemma Fryatt,Alexei Verkhratsky,Diego Gomez-Nicola,Arthur M Butt

doi:10.3389/fncel.2020.575082

Abstract

Myelin disruption is a feature of natural aging and Alzheimer’s disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Here, we examined age-related changes in OPCs in APP/PS1 mice, a model for AD-like pathology, compared with non-transgenic (Tg) age-matched controls. The analysis was performed in the CA1 area of the hippocampus following immunolabeling for NG2 with the nuclear dye Hoescht, to identify OPC and OPC sister cells, a measure of OPC replication. The results indicate a significant decrease in the number of OPCs at 9 months in APP/PS1 mice, compared to age-matched controls, without further decline at 14 months. Also, the number of OPC sister cells declined significantly at 14 months in APP/PS1 mice, which was not observed in age-matched controls. Notably, OPCs also displayed marked morphological changes at 14 months in APP/PS1 mice, characterized by an overall shrinkage of OPC process domains and increased process branching. The results indicate that OPC disruption is a pathological sign in the APP/PS1 mouse model of AD.

Highlights

Alzheimer’s disease (AD) is the most common type of dementia and it is characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid-β (Aβ) plaques (Braak and Braak, 1991)
Oligodendrocyte progenitor cells (OPCs) are responsible for the life-long generation of oligodendrocytes, required to myelinate new connections formed in response to new life experiences, and to replace myelin lost in pathology (Young et al, 2013; McKenzie et al, 2014; Xiao et al, 2016; Hughes et al, 2018)
We used NG2 immunolabeling to identify adult oligodendrocyte progenitor cells (OPCs) (Nishiyama et al, 2016) in the CA1 area of the hippocampus (Figure 1); NG2 is expressed by pericytes, which are directly applied to blood vessels and readily distinguished from OPCs, which are distinguished by their complex process bearing morphology (Hamilton et al, 2010)

Summary

INTRODUCTION

Alzheimer’s disease (AD) is the most common type of dementia and it is characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid-β (Aβ) plaques (Braak and Braak, 1991). Early changes in OPCs may be a pathological sign and underlie myelin loss in mouse models of AD-like pathology (Mitew et al, 2010; Rivera et al, 2016; Vanzulli et al, 2020). This possibility is supported by immunostaining of post-mortem AD brain showing changes in NG2 immunoreactivity in individuals with high Aβ plaque load (Nielsen et al, 2013). The APP/PS1 transgenic mouse expresses familial AD-causing mutated forms of human APP (APPswe, Swedish familial AD-causing mutation) and presenilin (PS1dE9) and is used extensively as a model for AD-like pathology (Borchelt et al, 1997). This study identifies pathological changes in OPCs in the APP/PS1 mouse model of AD

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

ETHICS STATEMENT