Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease
Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease
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.
Alzheimer's disease, Amyloid β, Astrocyte, Glia, Hippocampus, OPC, Oligodendrocyte progenitor cell
130-139
Vanzulli, Ilaria
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Papanikolaou, Maria
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Chacon De La Rocha, Irene
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Pieropan, Francesca
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Rivera, Andrea D.
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Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Verkhratsky, Alexei
21bff429-df7a-41da-8481-77e1d6f78cc1
Rodriguez, Jose Julio
3a8721dc-61dc-4f5f-aee8-fc9b1b1d8796
Butt, Arthur M.
381a0c45-e817-4f3c-90d9-3f8cf020fd12
October 2020
Vanzulli, Ilaria
381ccc52-b1b9-4ac9-bace-9291ded1a745
Papanikolaou, Maria
77350788-156c-4252-b1b2-5431af83ba94
Chacon De La Rocha, Irene
8645027e-ee17-474c-9396-35c25ed65cad
Pieropan, Francesca
386bd8e6-8d88-477c-9fbb-c3b937b03479
Rivera, Andrea D.
86ac60f6-43fc-45c5-8922-6ba1f25242d7
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Verkhratsky, Alexei
21bff429-df7a-41da-8481-77e1d6f78cc1
Rodriguez, Jose Julio
3a8721dc-61dc-4f5f-aee8-fc9b1b1d8796
Butt, Arthur M.
381a0c45-e817-4f3c-90d9-3f8cf020fd12
Vanzulli, Ilaria, Papanikolaou, Maria, Chacon De La Rocha, Irene, Pieropan, Francesca, Rivera, Andrea D., Gomez-Nicola, Diego, Verkhratsky, Alexei, Rodriguez, Jose Julio and Butt, Arthur M.
(2020)
Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease.
Neurobiology of Aging, 94, .
(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.
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Accepted/In Press date: 31 May 2020
e-pub ahead of print date: 7 June 2020
Published date: October 2020
Additional Information:
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Keywords:
Alzheimer's disease, Amyloid β, Astrocyte, Glia, Hippocampus, OPC, Oligodendrocyte progenitor cell
Identifiers
Local EPrints ID: 441346
URI: http://eprints.soton.ac.uk/id/eprint/441346
ISSN: 0197-4580
PURE UUID: 895ede9d-6502-4c86-b759-ddae8fe502b0
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Date deposited: 10 Jun 2020 16:30
Last modified: 06 Jun 2024 01:48
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Contributors
Author:
Ilaria Vanzulli
Author:
Maria Papanikolaou
Author:
Irene Chacon De La Rocha
Author:
Francesca Pieropan
Author:
Andrea D. Rivera
Author:
Alexei Verkhratsky
Author:
Jose Julio Rodriguez
Author:
Arthur M. Butt
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