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

• Published in: Neurobiology of aging 2020-10, Vol.94, p.130-139
• Main Authors: Vanzulli, Ilaria, Papanikolaou, Maria, De-La-Rocha, Irene Chacon, Pieropan, Francesca, Rivera, Andrea D., Gomez-Nicola, Diego, Verkhratsky, Alexei, Rodríguez, José Julio, Butt, Arthur M.
• Format: Article
• Language: English
• Subjects: Aging - pathology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid β; Animals; Astrocyte; Atrophy; Disease Models, Animal; Female; Glia; Hippocampus; Hippocampus - pathology; Hypertrophy; Male; Mice, Inbred C57BL; Mice, Transgenic; Myelin Sheath - metabolism; Myelin Sheath - pathology; Oligodendrocyte progenitor cell; Oligodendroglia - pathology; OPC; Stem Cells - pathology
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2020.05.016

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. [Display omitted] •Life-long generation of myelin is the function of adult oligodendrocyte progenitor cells (OPCs).•Age-related loss of myelin is accelerated in the 3xTg-AD mouse model of Alzheimer's disease (AD).•OPCs are disrupted at an early stage of 3xTg-AD.•Dysregulation of OPC and myelin loss are important biomarkers for AD-like pathology.