Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer's disease

Irene Chacon De-La-Rocha,Arthur M Butt,Maria Papanikolaou,Alexei Verkhratsky,José Julio Rodríguez,Andrea D Rivera,Ilaria Vanzulli,Diego Gomez-Nicola,Francesca Pieropan

doi:10.1016/j.neurobiolaging.2020.05.016

Abstract

There is increasing evidence that myelin disruption is related to cognitive decline in Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by adult oligodendrocyte progenitor cells (OPCs), also known as NG2-glia. To address whether alterations in myelination are related to age-dependent changes in OPCs, we analyzed NG2 and myelin basic protein (MBP) immunolabelling in the hippocampus of 3×Tg-AD mice at 6 and 24 months of age, compared with non-Tg age-matched controls. There was an age-related decrease in MBP immunostaining and OPC density, together with a decline in the number of OPC sister cells, a measure of OPC replication. Notably, the loss of myelin and OPC sister cells occurred earlier at 6 months in 3xTg-AD, suggesting accelerated aging, although there was not a concomitant decline in OPC numbers at this age, suggesting the observed changes in myelin were not a consequence of replicative exhaustion, but possibly of OPC disruption or senescence. In line with this, a key finding is that compared to age-match controls, OPC displayed marked morphological atrophy at 6 months in 3xTg-AD followed by morphological hypertrophy at 24 months, as deduced from significant changes in total cell surface area, total cell volume, somata volume and branching of main processes. Moreover, we show that hypertrophic OPCs surround and infiltrate amyloid-β (Aβ) plaques, a key pathological hallmark of AD. The results indicate that OPCs undergo complex age-related remodeling in the hippocampus of the 3xTg-AD mouse model. We conclude that OPC disruption is an early pathological sign in AD and is a potential factor in accelerated myelin loss and cognitive decline.

Highlights

Alzheimer's disease (AD) is a neurodegenerative disease characterised by age-related decline in learning, memory and cognition.Neuropathological hallmarks of AD are amyloid b (Ab) plaques and neurofibrillary tangles (NFTs)
Disruption of oligodendrocytes and myelin is an early event in the hippocampus of 3xTg-AD mice (Desai et al, 2009, 2010), but it is unclear how this is related to age-related changes in oligodendrocyte progenitor cells (OPCs), which are responsible for life-long generation of myelinating oligodendrocytes (Young et al, 2013)
NG2-positive OPCs were widely distributed throughout the hippocampus of both 3xTg-AD and non-Tg mice (Fig. 1Ai-iv), and cell counts indicated there was a decrease in the overall numerical density of OPCs between 6 months and 24 months in both 3xTg-Ad and non-Tg controls (Fig. 1Av, unpaired t-tests)

Summary

Introduction

Alzheimer's disease (AD) is a neurodegenerative disease characterised by age-related decline in learning, memory and cognition.Neuropathological hallmarks of AD are amyloid b (Ab) plaques and neurofibrillary tangles (NFTs). Alzheimer's disease (AD) is a neurodegenerative disease characterised by age-related decline in learning, memory and cognition. Myelin disruption is prominent in AD (Bartzokis, 2011), while myelin loss may predict AD onset and neurodegenerative changes in humans (Brickman et al, 2015), as well as in animal models of AD (Desai et al, 2009). Disruption of myelination is a feature of AD, the underlying causes are unresolved. In the CNS, myelin is produced by oligodendrocytes, which are generated from oligodendrocyte progenitor cells (OPCs) (Rivers et al, 2008; Zhu et al, 2011), known as NG2-glia or synantocytes (Butt et al, 2005). OPCs are identified by their expression of the membrane proteoglycan NG2 (Cspg4) (Stallcup, 1981), and are

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