CoChat
Sign Up
Cited by 130Neurogenesis and neuroplasticity mechanismsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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

Open access
Vanzulli, Ilaria, Papanikolaou, Maria, De-La-Rocha, Irene Chacon, Pieropan, Francesca, Rivera, Andrea D., Gomez-Nicola, Diego, Verkhratsky, Alexei, Rodríguez, José Julio +1 more·2020·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2020.05.016PMC PMC7453384
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.neurobiolaging.2020.05.016

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The early epoch features losses of oligodendrocytes and a dramatic increase in OPC differentiation and remyelination factors that may represent a compensatory response like that seen in models of oligodendrocyte loss.

    “This epoch also features losses of oligodendrocytes and a dramatic increase in OPC differentiation and remyelination factors that may represent a compensatory response like that seen in models of oligodendrocyte loss86,87.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [87]

    The Discussion (page unavailable) reports early myelin loss and reduced OPC self-renewal in 3xTg-AD mice. It does not report early losses of oligodendrocytes or a dramatic increase in OPC differentiation and remyelination factors; instead, it suggests reduced differentiation may contribute to declining myelination. The proposed compensatory response is not established by this paper. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 63 · Cited by 130

Research works printed but not linked: 49

  1. Bartzokis G. Alzheimer's disease as homeostatic responses to age-related myelin breakdown Neurobiol. Aging 32 2011 1341 1371 19775776 PMC3128664
  2. Belfiore R. Rodin A. Ferreira E. Velazquez R. Branca C. Caccamo A. Oddo S. Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice Aging Cell 18 2019 e12873 30488653 PMC6351836
  3. Bergles D.E. Roberts J.D. Somogyi P. Jahr C.E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus Nature 405 2000 187 191 10821275
  4. Boda E. Di Maria S. Rosa P. Taylor V. Abbracchio M.P. Buffo A. Early phenotypic asymmetry of sister oligodendrocyte progenitor cells after mitosis and its modulation by aging and extrinsic factors Glia 63 2014 271 286 25213035
  5. Brickman A.M. Zahodne L.B. Guzman V.A. Narkhede A. Meier I.B. Griffith E. Provenzano F.A. Schupf N. Manly J.J. Stern Y. Luchsinger J.A. Mayeux R. Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer’s disease incidence Neurobiol. Aging 36 2015 27 32 25155654 PMC4268124
  6. Butt A.M. De La Rocha I.C. Rivera A. Oligodendroglial cells in Alzheimer's disease Adv. Exp. Med. Biol. 1175 2019 325 333 31583593
  7. Butt A.M. Hamilton N. Hubbard P. Pugh M. Ibrahim M. Synantocytes: the fifth element J. Anat. 207 2005 695 706 16367797 PMC1571581
  8. Chakroborty S. Hill E.S. Christian D.T. Helfrich R. Riley S. Schneider C. Kapecki N. Mustaly-Kalimi S. Seiler F.A. Peterson D.A. West A.R. Vertel B.M. Frost W.N. Stutzmann G.E. Reduced presynaptic vesicle stores mediate cellular and network plasticity defects in an early-stage mouse model of Alzheimer’s disease Mol. Neurodegener. 14 2019 7 30670054 PMC6343260
  9. Chen T.J. Kula B. Nagy B. Barzan R. Gall A. Ehrlich I. Kukley M. In vivo regulation of oligodendrocyte precursor cell proliferation and differentiation by the AMPA-receptor subunit GluA2 Cell Rep. 25 2018 852 861 30355492
  10. Chvátal A. Anderová M. Hock M. Prajerová I. Neprasová H. Chvátal V. Kirchhoff F. Syková E. Three-dimensional confocal morphometry reveals structural changes in astrocyte morphology in situ J. Neurosci. Res. 85 2007 260 271 17086549
  11. Clark J.K. Furgerson M. Crystal J.D. Fechheimer M. Furukawa R. Wagner J.J. Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice Neurobiol. Learn Mem. 125 2015 152 162 26385257 PMC4648633
  12. Crimins J.L. Pooler A. Polydoro M. Luebke J.I. Spires-Jones T.L. The intersection of amyloid beta and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer's disease Ageing Res. Rev. 12 2013 757 763 23528367 PMC3735866
  13. Desai M.K. Guercio B.J. Narrow W.C. Bowers W.J. An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction Glia 59 2011 627 640 21294162 PMC3045399
  14. Desai M.K. Sudol K.L. Janelsins M.C. Mastrangelo M.A. Frazer M.E. Bowers W.J. Triple-transgenic Alzheimer's disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology Glia 57 2009 54 65 18661556 PMC2584762
  15. Dong Y.X. Zhang H.Y. Li H.Y. Liu P.H. Sui Y. Sun X.H. Association between Alzheimer's disease pathogenesis and early demyelination and oligodendrocyte dysfunction Neural Regen. Res. 13 2018 908 914 29863022 PMC5998637
  16. Fischer F.U. Wolf D. Scheurich A. Fellgiebel A. Altered whole-brain white matter networks in preclinical Alzheimer's disease Neuroimage. Clin. 8 2015 660 666 26288751 PMC4536470
  17. Horiuchi M. Maezawa I. Itoh A. Wakayama K. Jin L.W. Itoh T. Decarli C. Amyloid β1-42 oligomer inhibits myelin sheet formation in vitro Neurobiol. Aging 33 2012 499 509 20594620 PMC3013291
  18. Hoy A.R. Ly M. Carlsson C.M. Okonkwo O.C. Zetterberg H. Blennow K. Sager M.A. Asthana S. Johnson S.C. Alexander A.L. Bendlin B.B. Microstructural white matter alterations in preclinical Alzheimer’s disease detected using free water elimination diffusion tensor imaging PLoS One 12 2017 e0173982 28291839 PMC5349685
  19. Hughes E.G. Orthmann-Murphy J.L. Langseth A.J. Bergles D.E. Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex Nat. Neurosci. 21 2018 696 706 29556025 PMC5920726
  20. Ihara M. Polvikoski T.M. Hall R. Slade J.Y. Perry R.H. Oakley A.E. Englund E. O’Brien J.T. Ince P.G. Kalaria R.N. Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies Acta Neuropathol. 119 2010 579 589 20091409 PMC2849937
  21. Kang S.H. Fukaya M. Yang J.K. Rothstein J.D. Bergles D.E. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration Neuron 68 2010 668 681 21092857 PMC2989827
  22. Kulijewicz-Nawrot M. Syková E. Chvátal A. Verkhratsky A. Rodríguez J.J. Astrocytes and glutamate homoeostasis in Alzheimer's disease: a decrease in glutamine synthetase, but not in glutamate transporter-1, in the prefrontal cortex ASN Neuro. 5 2013 273 282 24059854 PMC3791522
  23. Levine J. The reactions and role of NG2 glia in spinal cord injury Brain Res. 1638 2016 199 208 26232070 PMC4732922
  24. Li W. Tang Y. Fan Z. Meng Y. Yang G. Luo J. Ke Z.-J. Autophagy is involved in oligodendroglial precursor-mediated clearance of amyloid peptide Mol. Neurodegener. 8 2013 27 23938027 PMC3751621
  25. Mastrangelo M.A. Bowers W.J. Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice BMC Neurosci. 9 2008 81 18700006 PMC2527610
  26. McKenzie A.T. Moyon S. Wang M. Katsyv I. Song W.M. Zhou X. Dammer E.B. Duong D.M. Aaker J. Zhao Y. Beckmann N. Wang P. Zhu J. Lah J.L. Seyfried N.T. Levey A.I. Katsel P. Haroutunian V. Schadt E.E. Popko B. Casaccia P. Zhang B. Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease Mol. Neurodegener. 12 2017 82 29110684 PMC5674813
  27. Mitew S. Kirkcaldie M.T. Halliday G.M. Shepherd C.E. Vickers J.C. Dickson T.C. Focal demyelination in Alzheimer's disease and transgenic mouse models Acta Neuropathol. 119 2010 567 577 20198482
  28. Nasrabady S.E. Rizvi B. Goldman J.E. Brickman A.M. White matter changes in Alzheimer's disease: a focus on myelin and oligodendrocytes Acta Neuropathol. Commun. 6 2018 22 29499767 PMC5834839
  29. Ndayisaba A. Kaindlstorfer C. Wenning G.K. Iron in neurodegeneration - cause or consequence? Front. Neurosci. 13 2019 180 30881284 PMC6405645
  30. Neumann B. Baror R. Zhao C. Segel M. Dietmann S. Rawji K.S. Foerster S. McClain C.R. Chalut K. van Wijngaarden P. Franklin R.J.M. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells Cell Stem Cell. 25 2019 473 485.e8 31585093 PMC6863391
  31. Nie X. Falangola M.F. Ward R. McKinnon E.T. Helpern J.A. Nietert P.J. Jensen J.H. Diffusion MRI detects longitudinal white matter changes in the 3xTg-AD mouse model of Alzheimer’s disease Magn. Reson. Imaging 57 2019 235 242 30543850 PMC6331227
  32. Nielsen H.M. Ek D. Avdic U. Orbjörn C. Hansson O. Veerhuis R. Rozemuller A.Jm. Brun A. Minthon L. Wennström M. Netherlands Brain Bank NG2 cells, a new trail for Alzheimer’s disease mechanisms? Acta Neuropathol. Commun. 1 2013 7 24252600 PMC4046664
  33. Nielsen H.M. Mulder S.D. Beliën J.A. Musters R.J. Eikelenboom P. Veerhuis R. Astrocytic A beta 1-42 uptake is determined by A beta-aggregation state and the presence of amyloid-associated proteins Glia 58 2010 1235 1246 20544859
  34. Olabarria M. Noristani H.N. Verkhratsky A. Rodríguez J.J. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease Glia 58 2010 831 838 20140958
  35. Ong W.Y. Levine J.M. A light and electron microscopic study of NG2 chondroitin sulfate proteoglycan-positive oligodendrocyte precursor cells in the normal and kainate-lesioned rat hippocampus Neuroscience 92 1999 83 95 10392832
  36. Rivera A. Vanzuli I. Arellano J.J. Butt A. Decreased regenerative capacity of oligodendrocyte progenitor cells (NG2-Glia) in the ageing brain: a vicious cycle of synaptic dysfunction, myelin loss and neuronal disruption? Curr. Alzheimer Res. 13 2016 413 418 26567743
  37. Rivers L.E. Young K.M. Rizzi M. Jamen F. Psachoulia K. Wade A. Kessaris N. Richardson W.D. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice Nat. Neurosci. 11 2008 1392 1401 18849983 PMC3842596
  38. Rodríguez J.J. Butt A.M. Gardenal E. Parpura V. Verkhratsky A. Complex and differential glial responses in Alzheimer's disease and ageing Curr. Alzheimer Res. 13 2016 343 358 26923267
  39. Rodríguez J.J. Jones V.C. Tabuchi M. Allan S.M. Knight E.M. LaFerla F.M. Oddo S. Verkhratsky A. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease PLoS One 3 2008 e2935 18698410 PMC2492828
  40. Rodríguez J.J. Terzieva S. Olabarria M. Lanza R.G. Verkhratsky A. Enriched environment and physical activity reverse astrogliodegeneration in the hippocampus of AD transgenic mice Cell Death Dis. 4 2013 e678 23788035 PMC3702309
  41. Roher A.E. Weiss N. Kokjohn T.A. Kuo Y.M. Kalback W. Anthony J. Watson D. Luehrs D.C. Sue L. Walker D. Emmerling M. Goux W. Beach T. Increased A beta peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer’s disease Biochemistry 41 2002 11080 11090 12220172
  42. Segel M. Neumann B. Hill M.F.E. Weber I.P. Viscomi C. Zhao C. Young A. Agley C.C. Thompson A.J. Gonzalez G.A. Sharma A. Holmqvist S. Rowitch D.H. Franze K. Franklin R.J.M. Chalut K.J. Niche stiffness underlies the ageing of central nervous system progenitor cells Nature 573 2019 130 134 31413369 PMC7025879
  43. Sim F.J. Zhao C. Penderis J. Franklin R.J. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation J. Neurosci. 22 2002 2451 2459 11923409 PMC6758320
  44. Stallcup W.B. The NG2 antigen, a putative lineage marker: immunofluorescent localization in primary cultures of rat brain Dev. Biol. 83 1981 154 165 7016634
  45. Stassart R.M. Mobius W. Nave K.A. Edgar J.M. The axon-myelin unit in development and degenerative disease Front. Neurosci. 12 2018 467 30050403 PMC6050401
  46. Wang R. Reddy P.H. Role of glutamate and NMDA receptors in Alzheimer's disease J. Alzheimers Dis. 57 2017 1041 1048 27662322 PMC5791143
  47. Yin F. Sancheti H. Patil I. Cadenas E. Energy metabolism and inflammation in brain aging and Alzheimer's disease Free Radic. Biol. Med. 100 2016 108 122 27154981 PMC5094909
  48. Zhan X. Jickling G.C. Ander B.P. Stamova B. Liu D. Kao P.F. Zelin M.A. Jin L.W. DeCarli C. Sharp F.R. Myelin basic protein associates with AbetaPP, Abeta1-42, and amyloid plaques in cortex of Alzheimer’s disease brain J. Alzheimers Dis. 44 2015 1213 1229 25697841 PMC4422390
  49. Zhu X. Hill R.A. Nishiyama A. NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord Neuron Glia Biol. 4 2008 19 26 19006598

Authors
Vanzulli, I., Papanikolaou, M., De-La-Rocha, I. C., Pieropan, F., Rivera, A. D., Gomez-Nicola, D., Verkhratsky, A., Rodríguez, J. J., & Butt, A. M.
Affiliations
  • University of Portsmouth (GB)
  • Ikerbasque (ES)
Corresponding author
Butt, Arthur M.
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2020-10
Volume
94
Pages
130-139
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2020.05.016
PMC
PMC7453384
OpenAlex
W3033481761
Cited by
130
References
63
Citations by year
2026: 6 · 2025: 33 · 2024: 23 · 2023: 22 · 2022: 22 · 2021: 18 · 2020: 6
FWCI
6.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Aging (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • Communities in ADDI (Universidad del Pais Vasco) (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • Hispana (submittedVersion, cc-by)
Funders
  • Medical Research Council
  • Alzheimer’s Research UK
  • Biotechnology and Biological Sciences Research Council
  • FP7 People: Marie-Curie Actions
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
oligodendrocyte precursor cells, NG2 glia, Alzheimer's disease, 3xTg-AD mice, demyelination, myelin basic protein, hippocampus, amyloid plaques, cognitive decline, aging, myelination
MeSH terms
Aging, Alzheimer Disease, Animals, Atrophy, Disease Models, Animal, Female, Hippocampus, Hypertrophy, Male, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Oligodendroglia, Stem Cells, Amyloid beta-Peptides

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review