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Cited by 324Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice

Open access
Kraft, Andrew W., Hu, Xiaoyan, Yoon, Hyejin, Yan, Ping, Xiao, Qingli, Wang, Yan, Gil, So Chon, Brown, Jennifer +7 more·2013·The FASEB Journal
DOI 10.1096/fj.12-208660PMC PMC3528309
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Abstract

The accumulation of aggregated amyloid‐β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation—glial fibrillary acid protein ( Gfap ) and vimentin ( Vim )—in transgenic mice expressing mutant human amyloid precursor protein and presenilin‐1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap –/– Vim –/– mice had twice the plaque load of APP/PS1 Gfap +/+ Vim +/+ mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation. Astrocyte morphology was markedly altered by the deletions: wild‐type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap –/– Vim –/– astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2‐ to 3‐fold higher than APP/PS1 Gfap +/+ Vim +/+ mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque‐related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque.—Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., Lee, J.‐M. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 27, 187–198 (2013). www.fasebj.org

AI snapshot

Written from the paper’s full text.

TL;DR

Deleting astrocyte intermediate filament genes *Gfap* and *Vim* in APP/PS1 mice increased amyloid plaque load and dystrophic neurites without changing APP processing or soluble/interstitial Aβ levels. The results suggest that activated astrocytes limit plaque growth and plaque-related neuritic dystrophy, likely requiring intimate astrocyte–plaque contact.

Key findings

  • APP/PS1 *Gfap*−/−*Vim*−/− mice had twice the plaque load of APP/PS1 *Gfap*+/+*Vim*+/+ mice at 8 and 12 mo of age, with no difference at 4 mo.
  • APP expression, soluble Aβ, interstitial fluid Aβ levels, and ISF Aβ half-life were unchanged, suggesting no effect on APP processing or Aβ generation.
  • Dystrophic neurites were 2- to 3-fold higher in APP/PS1 *Gfap*−/−*Vim*−/− mice than in APP/PS1 *Gfap*+/+*Vim*+/+ mice, even after normalization for amyloid load.
  • Wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas *Gfap*−/−*Vim*−/− astrocytes showed little process hypertrophy and lacked contact with adjacent plaques; astrocyte density was unchanged.
  • Microglial density was slightly higher and microglia–plaque overlap was two-fold greater in APP/PS1 *Gfap*−/−*Vim*−/− mice, but plaque burden still increased.

Methods

  • APPswe/PS1ΔE9 transgenic mice were crossed with *Gfap*−/−*Vim*−/− mice over 3 generations to produce APP/PS1 *Gfap*+/+*Vim*+/+ and APP/PS1 *Gfap*−/−*Vim*−/− mice on the same mixed background.
  • Brains were analyzed by immunohistochemistry, immunofluorescence, X-34 plaque staining, Aβ ELISA, real-time qPCR, Western blotting, in vivo microdialysis, AAV-GFAP-GFP stereotactic injection, plaque quantification, and unbiased stereology.
  • Comparisons used two-tailed Student’s *t* test or Mann-Whitney *U* test; plaque quantification used n=9–10/group, stereology n=5/group, and AAV injection n=3/group.

Limitations

  • The paper states that the precise mechanism for the contact-dependent, plaque-suppressing effect is unclear, and that direct evidence for astrocyte phagocytosis of plaque material is lacking.
  • The paper states it cannot discount the possibility that activated astrocytes remove dystrophic neurites, meaning the observed changes could reflect impaired clearance rather than exacerbated neurotoxicity.
  • Evident from the text: findings are limited to the APP/PS1 mouse model and genetic deletion approach; proposed mechanisms such as delivery of Aβ-degrading proteases or altered vascular Aβ transport were not directly tested.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1096/fj.12-208660

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

33 of 74 cited sources checked · 16 supported · 1 flagged · accuracy not yet measured

  • Premisecitation
    § DISCUSSION

    Vim requires a second intermediate filament protein (e.g., nestin or synemin in astrocytes) to form a network.

    “but Vim requires a second intermediate filament protein (e.g., nestin or synemin in astrocytes) to form a network (20, 24).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [20] 20. Eliasson C., Sahlgren C., Berthold C. H., Stakeberg J., Celis J. E., Betsholtz C., Eriksson J. E., Pekny M. (1999) Intermediate filament protein partnership in astrocytes. J. Biol. Chem. 274, 23996–24006 [DOI] [PubMed] [Google Scholar] source
    • cites [24] 24. Jing R., Wilhelmsson U., Goodwill W., Li L., Pan Y., Pekny M., Skalli O. (2007) Synemin is expressed in reactive astrocytes in neurotrauma and interacts differentially with vimentin and GFAP intermediate filament networks. J. Cell Sci. 120, 1267–1277 [DOI] [PubMed] [Google Scholar] source

      The Introduction (page unavailable in our copy) says that vimentin and GFAP can each polymerize on their own; it is synemin that cannot assemble into intermediate filaments on its own and can copolymerize with vimentin. The claim reverses which protein requires a partner. (LLM, conf=0.91)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation
    § RESULTS

    Immunostaining with individual antibodies cannot reveal the full extent of astrocyte morphology.

    “Because immunostaining with individual antibodies cannot reveal the full extent of astrocyte morphology (16), we expressed GFP in astrocytes in vivo to observe the complete cellular profile of the cells.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] 16. Wilhelmsson U., Bushong E. A., Price D. L., Smarr B. L., Phung V., Terada M., Ellisman M. H., Pekny M. (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc. Natl. Acad. Sci. U. S. A. 103, 17513–17518 [DOI] [PMC free article] [PubMed] [Google Scholar] source
  • Premisecitation
    § DISCUSSION

    The effects of acute central nervous system injury are comparable in Gfap−/−, Vim−/−, and wild-type mice.

    “Further, the effects of acute central nervous system injury are comparable in Gfap−/−, Vim−/−, and wild-type mice (22, 32).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [22] 22. Pekny M., Johansson C. B., Eliasson C., Stakeberg J., Wallen A., Perlmann T., Lendahl U., Betsholtz C., Berthold C. H., Frisen J. (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145, 503–514 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Discussion (Defective CNS Scar Formation) says scar formation after brain or spinal cord injury was comparable in wild-type, GFAP−/−, and vimentin−/− mice. But the Results (Responses to Brain Injury) report weaker, diffuse nestin immunoreactivity after injury in vimentin−/− mice, so the broader claim that the effects of injury were comparable is not fully supported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [32] 32. Li L., Lundkvist A., Andersson D., Wilhelmsson U., Nagai N., Pardo A. C., Nodin C., Stahlberg A., Aprico K., Larsson K., Yabe T., Moons L., Fotheringham A., Davies I., Carmeliet P., Schwartz J. P., Pekna M., Kubista M., Blomstrand F., Maragakis N., Nilsson M., Pekny M. (2008) Protective role of reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab. 28, 468–481 [DOI] [PubMed] [Google Scholar] source
  • Premisecitation
    § DISCUSSION

    Transcriptome profiling of different cell types in mouse brain revealed that astrocytes express high levels of phagocytic genes, including Draper/Megf10 and Mertk/integrin αvβ5, which are involved in engulfing debris coated by specific opsins.

    “Transcriptome profiling of different cell types in mouse brain revealed that astrocytes express high levels of phagocytic genes, including Draper/Megf10 and Mertk/integrin αvβ5, which are involved in engulfing debris coated by specific opsins (60).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [60] 60. Cahoy J. D., Emery B., Kaushal A., Foo L. C., Zamanian J. L., Christopherson K. S., Xing Y., Lubischer J. L., Krieg P. A., Krupenko S. A., Thompson W. J., Barres B. A. (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 [DOI] [PMC free article] [PubMed] [Google Scholar] source
  • Premisecitation
    § DISCUSSION

    Deletion of both Gfap and Vim appears to primarily affect astrocytes.

    “The deletion of both genes appears to primarily affect astrocytes (for review, see refs. 15, 53).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [15] 15. Pekny M., Nilsson M. (2005) Astrocyte activation and reactive gliosis. Glia 50, 427–434 [DOI] [PubMed] [Google Scholar] source
    • cites [53] 53. Pekny M., Pekna M. (2004) Astrocyte intermediate filaments in CNS pathologies and regeneration. J. Pathol. 204, 428–437 [DOI] [PubMed] [Google Scholar] source

      The ‘Astrocytes, IFs, and reactive gliosis’ section reports that astrocytes in mice lacking both GFAP and vimentin are completely devoid of intermediate filaments. The ‘Astroglial cells without IFs’ section also reports effects in retinal Müller cells; the review does not establish that astrocytes are affected primarily rather than other cell types. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 32
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Absence of GFAP and/or Vim in mice has no major effect under physiological conditions.

    “Absence of GFAP and/or Vim in mice has no major effect under physiological conditions (17–20), reflecting the role of intermediate filament (nanofilament) system as a signaling platform in situations connected with cellular stress (21).”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [17] 17. Pekny M., Leveen P., Pekna M., Eliasson C., Berthold C. H., Westermark B., Betsholtz C. (1995) Mice lacking glial fibrillary acidic protein display astrocytes devoid of intermediate filaments but develop and reproduce normally. EMBO J. 14, 1590–1598 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [18] 18. Gomi H., Yokoyama T., Fujimoto K., Ikeda T., Katoh A., Itoh T., Itohara S. (1995) Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions. Neuron 14, 29–41 [DOI] [PubMed] [Google Scholar] source
    • cites [19] 19. Colucci-Guyon E., Portier M. M., Dunia I., Paulin D., Pournin S., Babinet C. (1994) Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 79, 679–694 [DOI] [PubMed] [Google Scholar] source
    • cites [20] 20. Eliasson C., Sahlgren C., Berthold C. H., Stakeberg J., Celis J. E., Betsholtz C., Eriksson J. E., Pekny M. (1999) Intermediate filament protein partnership in astrocytes. J. Biol. Chem. 274, 23996–24006 [DOI] [PubMed] [Google Scholar] source
    • cites [21] 21. Pekny M., Lane E. B. (2007) Intermediate filaments and stress. Exp. Cell Res. 313, 2244–2254 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Astrocytes are activated in response to acute or chronic central nervous system injury, characterized by hypertrophy of proximal processes and up-regulation of GFAP and Vim.

    “Astrocytes are activated in response to acute or chronic central nervous system injury. The activated state is characterized by hypertrophy of proximal processes and up-regulation of the intermediate filament (nanofilament) proteins glial fibrillary acid protein (GFAP) and vimentin (Vim) (15, 16).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [15] 15. Pekny M., Nilsson M. (2005) Astrocyte activation and reactive gliosis. Glia 50, 427–434 [DOI] [PubMed] [Google Scholar] source
    • cites [16] 16. Wilhelmsson U., Bushong E. A., Price D. L., Smarr B. L., Phung V., Terada M., Ellisman M. H., Pekny M. (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc. Natl. Acad. Sci. U. S. A. 103, 17513–17518 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Results and Discussion report astrocyte activation after injury and thickening of the main GFAP-containing processes. The introductory passage (labeled Abstract in our copy; page unavailable) reports increased GFAP expression and intermediate filaments in reactive astrocytes, and names vimentin as an intermediate-filament marker, but does not specifically establish vimentin up-regulation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Increased gliosis induced by brain infusion of lipopolysaccharide or overexpression of interleukin-6 or interferon-γ markedly reduces amyloid plaque burden.

    “For example, increased gliosis induced by brain infusion of lipopolysaccharide (4) or overexpression of the inflammatory cytokine interleukin-6 (5) or interferon-γ (6) markedly reduces amyloid plaque burden.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [4] 4. DiCarlo G., Wilcock D., Henderson D., Gordon M., Morgan D. (2001) Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice. Neurobiol. Aging 22, 1007–1012 [DOI] [PubMed] [Google Scholar] source
    • cites [5] 5. Chakrabarty P., Jansen-West K., Beccard A., Ceballos-Diaz C., Levites Y., Verbeeck C., Zubair A. C., Dickson D., Golde T. E., Das P. (2009) Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 24, 548–559 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [6] 6. Chakrabarty P., Ceballos-Diaz C., Beccard A., Janus C., Dickson D., Golde T. E., Das P. (2010) IFN-γ promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J. Immunol. 184, 5333–5343 [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Attenuated reactive gliosis in Gfap−/−Vim−/− mice was connected with larger infarctions in focal brain ischemia and facilitated disease progression in Batten's disease.

    “Attenuated reactive gliosis in Gfap−/− Vim−/− mice was connected with larger infarctions in a mouse model of focal brain ischemia (32) and facilitated disease progression in a mouse model of Batten's disease (33).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] 32. Li L., Lundkvist A., Andersson D., Wilhelmsson U., Nagai N., Pardo A. C., Nodin C., Stahlberg A., Aprico K., Larsson K., Yabe T., Moons L., Fotheringham A., Davies I., Carmeliet P., Schwartz J. P., Pekna M., Kubista M., Blomstrand F., Maragakis N., Nilsson M., Pekny M. (2008) Protective role of reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab. 28, 468–481 [DOI] [PubMed] [Google Scholar] source
    • cites [33] 33. Macauley S. L., Pekny M., Sands M. S. (2011) The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis. J. Neurosci. 31, 15575–15585 [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Gfap−/−Vim−/− mice exhibit better posttraumatic regeneration of neuronal synapses and axons, increased baseline and posttraumatic neurogenesis, and improved functional recovery after spinal cord trauma.

    “Interestingly, Gfap−/−Vim−/− mice exhibit better posttraumatic regeneration of neuronal synapses (23) and axons (34), increased baseline and posttraumatic neurogenesis (35), and improved functional recovery after spinal cord trauma (36).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [23] 23. Wilhelmsson U., Li L., Pekna M., Berthold C. H., Blom S., Eliasson C., Renner O., Bushong E., Ellisman M., Morgan T. E., Pekny M. (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J. Neurosci. 24, 5016–5021 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [34] 34. Cho K. S., Yang L., Lu B., Feng Ma H., Huang X., Pekny M., Chen D. F. (2005) Re-establishing the regenerative potential of central nervous system axons in postnatal mice. J. Cell Sci. 118, 863–872 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [35] 35. Wilhelmsson U., Faiz M., de Pablo Y., Sjoqvist M., Andersson D., Widestrand A., Potokar M., Stenovec M., Smith P. L., Shinjyo N., Pekny T., Zorec R., Stahlberg A., Pekna M., Sahlgren C., Pekny M. (2012) Astrocytes negatively regulate neurogenesis through the Jagged1-mediated Notch pathway. Stem Cells 30, 2320–2329 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Gfap−/−Vim−/− mice support better integration of neural grafts in the retina and neuronal and astrocyte differentiation of neural stem cells transplanted in the hippocampus.

    “They also support better integration of neural grafts in the retina (37) and neuronal and astrocyte differentiation of neural stem cells transplanted in the hippocampus (38).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [37] 37. Kinouchi R., Takeda M., Yang L., Wilhelmsson U., Lundkvist A., Pekny M., Chen D. F. (2003) Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat. Neurosci. 6, 863–868 [DOI] [PubMed] [Google Scholar] source
    • cites [38] 38. Widestrand A., Faijerson J., Wilhelmsson U., Smith P. L., Li L., Sihlbom C., Eriksson P. S., Pekny M. (2007) Increased neurogenesis and astrogenesis from neural progenitor cells grafted in the hippocampus of GFAP−/− Vim−/− mice. Stem Cells 25, 2619–2627 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    After brain or spinal cord injury, reactive gliosis and the formation of glial scar are attenuated and the healing process is prolonged in Gfap−/−Vim−/− mice.

    “However, after brain or spinal cord injury, reactive gliosis and the formation of glial scar are attenuated and the healing process is prolonged (22).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] 22. Pekny M., Johansson C. B., Eliasson C., Stakeberg J., Wallen A., Perlmann T., Lendahl U., Betsholtz C., Berthold C. H., Frisen J. (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145, 503–514 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Results section on spinal cord injury and the Discussion section on defective CNS scar formation report less dense, fissured scars in GFAP−/−vim−/− mice, supporting impaired glial scar formation. The paper does not establish that healing after brain or spinal cord injury was prolonged: its Results say surviving mice’s brain wounds were sealed within three weeks, while the Discussion’s suggestion of slower wound closure concerns a preliminary in vitro assay. It also reports comparable astrocyte numbers and cell proliferation, so attenuated reactive gliosis as a whole is broader than the demonstrated scar defect. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Abstract

    Gfap−/−Vim−/− astrocytes are completely devoid of intermediate filaments because nestin and synemin cannot form intermediate filaments in the absence of both GFAP and Vim.

    “They are completely devoid of intermediate filaments since neither of the other two intermediate filament proteins expressed in reactive astrocytes, nestin and synemin, are able to form intermediate filaments in the absence of both GFAP and Vim (20, 22, 24).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [20] 20. Eliasson C., Sahlgren C., Berthold C. H., Stakeberg J., Celis J. E., Betsholtz C., Eriksson J. E., Pekny M. (1999) Intermediate filament protein partnership in astrocytes. J. Biol. Chem. 274, 23996–24006 [DOI] [PubMed] [Google Scholar] source
    • cites [22] 22. Pekny M., Johansson C. B., Eliasson C., Stakeberg J., Wallen A., Perlmann T., Lendahl U., Betsholtz C., Berthold C. H., Frisen J. (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145, 503–514 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The paper reports that GFAP−/−vim−/− astrocytes lack intermediate filaments in both quiescent and reactive states. In the Discussion section on altered nestin expression, it says that nestin fails to form filaments on its own in these astrocytes. Our copy does not address synemin or establish that it cannot form filaments without GFAP and vimentin. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [24] 24. Jing R., Wilhelmsson U., Goodwill W., Li L., Pan Y., Pekny M., Skalli O. (2007) Synemin is expressed in reactive astrocytes in neurotrauma and interacts differentially with vimentin and GFAP intermediate filament networks. J. Cell Sci. 120, 1267–1277 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Astrocytes of Gfap−/−Vim−/− mice in the injured area do not develop the characteristic hypertrophy of proximal processes.

    “On a cellular level, astrocytes of Gfap−/−Vim−/− mice in the injured area do not develop the characteristic hypertrophy of proximal processes (23).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] 23. Wilhelmsson U., Li L., Pekna M., Berthold C. H., Blom S., Eliasson C., Renner O., Bushong E., Ellisman M., Morgan T. E., Pekny M. (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J. Neurosci. 24, 5016–5021 [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Microglia migrate to amyloid plaques and may alter plaque growth dynamics in transgenic mouse models of AD.

    “More recent studies in transgenic mouse models of AD have shown that microglia migrate to amyloid plaques and may alter plaque growth dynamics (9–12).”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [9] 9. Mandrekar S., Jiang Q., Lee C. Y., Koenigsknecht-Talboo J., Holtzman D. M., Landreth G. E. (2009) Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J. Neurosci. 29, 4252–4262 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Discussion (page not provided) reports that microglia play a role in plaque dynamics in an AD transgenic mouse model and internalize plaque fragments. It does not say that microglia migrate to plaques, so that part of the citing sentence is not supported by this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [10] 10. Jiang Q., Lee C. Y., Mandrekar S., Wilkinson B., Cramer P., Zelcer N., Mann K., Lamb B., Willson T. M., Collins J. L., Richardson J. C., Smith J. D., Comery T. A., Riddell D., Holtzman D. M., Tontonoz P., Landreth G. E. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58, 681–693 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [11] 11. Meyer-Luehmann M., Spires-Jones T. L., Prada C., Garcia-Alloza M., de Calignon A., Rozkalne A., Koenigsknecht-Talboo J., Holtzman D. M., Bacskai B. J., Hyman B. T. (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451, 720–724 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [12] 12. Bolmont T., Haiss F., Eicke D., Radde R., Mathis C. A., Klunk W. E., Kohsaka S., Jucker M., Calhoun M. E. (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J. Neurosci. 28, 4283–4292 [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § DISCUSSION

    When Gfap and Vim are both deleted, astrocytes cannot form intermediate filament networks or display reactive morphology.

    “But when Gfap and Vim are both deleted, astrocytes cannot form intermediate filament networks or display reactive morphology (22, 23, 32).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [22] 22. Pekny M., Johansson C. B., Eliasson C., Stakeberg J., Wallen A., Perlmann T., Lendahl U., Betsholtz C., Berthold C. H., Frisen J. (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145, 503–514 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Abstract (page unavailable) says GFAP−/−vim−/− astrocytes cannot form intermediate filaments, even in their reactive state. The Discussion (page unavailable) reports defective scar formation and suggests reduced astrocytic process formation, but does not establish that these astrocytes cannot display reactive morphology at all. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] 23. Wilhelmsson U., Li L., Pekna M., Berthold C. H., Blom S., Eliasson C., Renner O., Bushong E., Ellisman M., Morgan T. E., Pekny M. (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J. Neurosci. 24, 5016–5021 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Introduction says GFAP/Vim-deficient astrocytes are completely devoid of intermediate filaments. But the Results and Figure 1 describe them as reactive astrocytes with altered morphology and limited process hypertrophy, not as unable to display any reactive morphology. Page numbers are not available in the supplied copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [32] 32. Li L., Lundkvist A., Andersson D., Wilhelmsson U., Nagai N., Pardo A. C., Nodin C., Stahlberg A., Aprico K., Larsson K., Yabe T., Moons L., Fotheringham A., Davies I., Carmeliet P., Schwartz J. P., Pekna M., Kubista M., Blomstrand F., Maragakis N., Nilsson M., Pekny M. (2008) Protective role of reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab. 28, 468–481 [DOI] [PubMed] [Google Scholar] source

  • Classified as probably not a substantial claim.

    Premisecitation
    § DISCUSSION

    In several models of acute central nervous system injury, deletion of the genes encoding GFAP and Vim suppresses morphological changes associated with astrocyte activation.

    “In several models of acute central nervous system injury, deletion of the genes encoding these proteins suppresses morphological changes associated with astrocyte activation (22, 23, 26, 30, 32, 36).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [22] 22. Pekny M., Johansson C. B., Eliasson C., Stakeberg J., Wallen A., Perlmann T., Lendahl U., Betsholtz C., Berthold C. H., Frisen J. (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145, 503–514 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Abstract and Discussion report impaired, less compact glial scars after brain and spinal cord injury in mice lacking both GFAP and vimentin. This supports an altered injury-associated morphology, but the paper does not show that astrocyte activation’s morphological changes are suppressed generally; it reports a normal injury-induced proliferation response and treats reduced astrocytic process formation as a possible explanation for the scar defect. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [23] 23. Wilhelmsson U., Li L., Pekna M., Berthold C. H., Blom S., Eliasson C., Renner O., Bushong E., Ellisman M., Morgan T. E., Pekny M. (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J. Neurosci. 24, 5016–5021 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [26] 26. Lu Y. B., Iandiev I., Hollborn M., Korber N., Ulbricht E., Hirrlinger P. G., Pannicke T., Wei E. Q., Bringmann A., Wolburg H., Wilhelmsson U., Pekny M., Wiedemann P., Reichenbach A., Kas J. A. (2011) Reactive glial cells: increased stiffness correlates with increased intermediate filament expression. FASEB J. 25, 624–631 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § RESULTS

    BDNF expression is increased in amyloid-associated astrocytes.

    “Previous work has shown BDNF expression is increased in amyloid-associated astrocytes (51)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [51] 51. Burbach G. J., Hellweg R., Haas C. A., Del Turco D., Deicke U., Abramowski D., Jucker M., Staufenbiel M., Deller T. (2004) Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. J. Neurosci. 24, 2421–2430 [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § DISCUSSION

    MMP-9 is capable of degrading amyloid fibrils in vitro and amyloid plaques in situ.

    “and that MMP-9 is capable of degrading amyloid fibrils in vitro and amyloid plaques in situ (61).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [61] 61. Yan P., Hu X., Song H., Yin K., Bateman R. J., Cirrito J. R., Xiao Q., Hsu F. F., Turk J. W., Xu J., Hsu C. Y., Holtzman D. M., Lee J. M. (2006) Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J. Biol. Chem. 281, 24566–24574 [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § DISCUSSION

    Under baseline conditions, Gfap−/−Vim−/− mice have astrocytes of normal appearance and grossly normal brain anatomy.

    “Under baseline conditions, however, Gfap−/−Vim−/− mice have astrocytes of normal appearance and grossly normal brain anatomy (22, 23, 32).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [22] 22. Pekny M., Johansson C. B., Eliasson C., Stakeberg J., Wallen A., Perlmann T., Lendahl U., Betsholtz C., Berthold C. H., Frisen J. (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145, 503–514 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Materials and Methods (Animals; page not available) says the double-mutant mice reached adulthood without overt anatomical defects, supporting the broad claim of grossly normal anatomy. Our copy does not establish that their astrocytes appeared normal under baseline conditions. Results (Dilated Blood Vessels; page not available) also documents abnormalities in the uninjured brain and spinal cord, so grossly normal should not be read as anatomically unchanged. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [23] 23. Wilhelmsson U., Li L., Pekna M., Berthold C. H., Blom S., Eliasson C., Renner O., Bushong E., Ellisman M., Morgan T. E., Pekny M. (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J. Neurosci. 24, 5016–5021 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Figure 1 and the Results (page not specified in our copy) report similar astrocyte morphology and process length in GFAP−/− Vim−/− and wild-type mice before lesion. The paper does not establish the broader claim that their brain anatomy is grossly normal. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [32] 32. Li L., Lundkvist A., Andersson D., Wilhelmsson U., Nagai N., Pardo A. C., Nodin C., Stahlberg A., Aprico K., Larsson K., Yabe T., Moons L., Fotheringham A., Davies I., Carmeliet P., Schwartz J. P., Pekna M., Kubista M., Blomstrand F., Maragakis N., Nilsson M., Pekny M. (2008) Protective role of reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab. 28, 468–481 [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § DISCUSSION

    GFAP and Vim are expressed at high levels in activated astrocytes and are critical for the activated phenotype.

    “The intermediate filament proteins GFAP and Vim are expressed at high levels in activated astrocytes and are critical for the activated phenotype.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [22] 22. Pekny M., Johansson C. B., Eliasson C., Stakeberg J., Wallen A., Perlmann T., Lendahl U., Betsholtz C., Berthold C. H., Frisen J. (1999) Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145, 503–514 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The paper’s Abstract (page not provided) states that astrocytes express high levels of GFAP and vimentin after CNS injury. It also reports that losing both proteins impairs glial scar formation, but it does not establish that they are critical for the activated phenotype as a whole: the double-deficient astrocytes are described as reactive, and the Discussion reports a normal proliferation response to injury. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] 23. Wilhelmsson U., Li L., Pekna M., Berthold C. H., Blom S., Eliasson C., Renner O., Bushong E., Ellisman M., Morgan T. E., Pekny M. (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J. Neurosci. 24, 5016–5021 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Introduction describes intermediate-filament upregulation as a hallmark of reactive astrocytes and proposes that it is crucial to activation. Figure 1 and the Results show that loss of GFAP and vimentin prevents process hypertrophy and endothelin B receptor upregulation after injury. The paper still calls the deficient astrocytes reactive, so it supports a role in specific features of the activated phenotype, not that these proteins are critical to the activated phenotype as a whole. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [32] 32. Li L., Lundkvist A., Andersson D., Wilhelmsson U., Nagai N., Pardo A. C., Nodin C., Stahlberg A., Aprico K., Larsson K., Yabe T., Moons L., Fotheringham A., Davies I., Carmeliet P., Schwartz J. P., Pekna M., Kubista M., Blomstrand F., Maragakis N., Nilsson M., Pekny M. (2008) Protective role of reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab. 28, 468–481 [DOI] [PubMed] [Google Scholar] source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § DISCUSSION

    Astrocyte endfeet line the abluminal aspect of endothelial cells and are important for the formation and maintenance of the blood-brain-barrier.

    “Astrocyte endfeet line the abluminal aspect of endothelial cells and are important for the formation and maintenance of the blood-brain-barrier (29).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] 29. Vardjan N., Gabrijel M., Potokar M., Svajger U., Kreft M., Jeras M., de Pablo Y., Faiz M., Pekny M., Zorec R. (2012) IFN-gamma-induced increase in the mobility of MHC class II compartments in astrocytes depends on intermediate filaments. J. Neuroinflammation 9, 144. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Background and Conclusions discuss astrocyte antigen presentation and MHC class II trafficking, not astrocyte endfeet or the blood–brain barrier. Searches for endfeet, endothelial cells, and blood–brain barrier formation and maintenance found no passage addressing the claim in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Microglia can internalize fibrillar Aβ in vitro and in vivo.

    “Although microglia can internalize fibrillar Aβ in vitro and in vivo”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [8] 8. Paresce D. M., Ghosh R. N., Maxfield F. R. (1996) Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor. Neuron 17, 553–565 [DOI] [PubMed] [Google Scholar] source
    • cites [12] 12. Bolmont T., Haiss F., Eicke D., Radde R., Mathis C. A., Klunk W. E., Kohsaka S., Jucker M., Calhoun M. E. (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J. Neurosci. 28, 4283–4292 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Introduction says microglia can phagocytose Aβ in culture, and the ‘Microglia uptake of injected dye’ section reports Aβ-positive particles inside microglia in vivo. But the Discussion explicitly says further study is needed to determine whether the internalized material is soluble Aβ or fibrillary amyloid. The source therefore supports Aβ uptake in both settings, not the claim that fibrillar Aβ is internalized in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Astrocytes may play an important role in the transport of Aβ into or out of the CNS through the astrocyte-vasculature interface.

    “Moreover, astrocytes may play an important role in the transport of Aβ into or out of the CNS through this important interface (63).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] 63. Askarova S., Yang X., Sheng W., Sun G. Y., Lee J. C. (2011) Role of Abeta-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A(2) activation in astrocytes and cerebral endothelial cells. Neuroscience 199, 375–385 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Introduction (page not available) says Aβ binding to RAGE regulates transport across the blood–brain barrier, and the paper identifies astrocytes as a component of that barrier. It does not say that astrocytes themselves transport Aβ into or out of the CNS through the astrocyte–vasculature interface. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data
    § Abstract

    APP expression and soluble and interstitial fluid Aβ levels were unchanged in APP/PS1 Gfap−/−Vim−/− mice compared with APP/PS1 Gfap+/+Vim+/+ mice.

    “APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap−/−Vim−/− astrocytes had little process hypertrophy and lacked contact with adjacent plaques.

    “Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap−/−Vim−/− astrocytes had little process hypertrophy and lacked contact with adjacent plaques.”
    • Also stated in: § RESULTS · plain
      “Astrocytic invasion of plaques is attenuated in APP/PS1 Gfap−/−Vim−/− mice”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Abstract

    APP/PS1 Gfap−/−Vim−/− mice had significantly greater Aβ plaque load and amyloid load in the cortex and hippocampus than APP/PS1 Gfap+/+Vim+/+ mice at 8 and 12 months but not 4 months; at 8 and 12 months plaque load was about twice.

    “The gene deletions increased amyloid plaque load: APP/PS1 Gfap−/−Vim−/− mice had twice the plaque load of APP/PS1 Gfap+/+Vim+/+ mice at 8 and 12 mo of age.”
    • Also stated in: § RESULTS · plain
      “Aβ load and amyloid load were significantly increased in the cortex and hippocampus of APP/PS1 Gfap−/−Vim−/− mice at 8 and 12 but not 4 mo of age (Fig. 1A–F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given
    § RESULTS

    Mice of both genotypes were grossly normal and fertile, without obvious behavioral or anatomical differences.

    “Mice of both genotypes were grossly normal and fertile, without obvious behavioral or anatomical differences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    At 8 and 12 mo, APP/PS1 Gfap−/−Vim−/− mice had significantly higher Aβ levels in the guanidine extract but not in the PBS fraction.

    “At 8 and 12 mo, APP/PS1 Gfap−/− Vim−/− mice had significantly higher Aβ levels in the guanidine extract but not in the PBS fraction (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Only APH-1b and MMP-9 showed significant, but modest, decreases (20-30% decrease) in mRNA levels in APP/PS1 Gfap−/−Vim−/− mice; transcript levels for all other genes were unchanged.

    “Only APH-1b and MMP-9 showed significant, but modest, decreases (20-30% decrease) in mRNA levels in the APP/PS1 Gfap−/−Vim−/− mice (Fig. 5A); transcript levels for all other genes were unchanged.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    No difference was observed in the pattern of synaptophysin immunoreactivity surrounding plaques or in the amount of synaptophysin or PSD95 mRNA between the cortices of each genotype.

    “Although Gfap/Vim gene deletion exacerbates neuritic dystrophy, we observed no difference in the pattern of synaptophysin immunoreactivity surrounding plaques and no difference in the amount of synaptophysin or PSD95 mRNA between the cortices of each genotype (Supplemental Fig. S3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    MMP-2 and MMP-9 showed no significant changes in APP/PS1 Gfap−/−Vim−/− mice, although pro-MMP9 and MMP9 showed a decreasing trend.

    “Similarly, MMP-2 and MMP-9 showed no significant changes in APP/PS1 Gfap−/−Vim−/− mice (Fig. 5D, E), although pro-MMP9 and MMP9 showed a decreasing trend.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    ApoE and apoJ (clusterin) showed no significant differences between genotypes.

    “ApoE and apoJ (clusterin) showed no significant differences (Fig. 5C, E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Astrocytes from APP/PS1 Gfap−/−Vim−/− mice did not exhibit process hypertrophy, and distal processes appeared as fine strands.

    “In contrast, astrocytes from APP/PS1 Gfap−/−Vim−/− mice did not exhibit process hypertrophy, and distal processes appeared as fine strands.”
    • Also stated in: § DISCUSSION · plain
      “Gfap−/−Vim−/− astrocytes lacked the hypertrophic processes observed in wild-type astrocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Abstract

    Gfap and Vim deletion did not alter APP expression, APP processing, or Aβ generation.

    “APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation.”
    • Also stated in: § RESULTS · hedged
      “Western blot analysis showed no differences between genotypes in APP expression and C-terminal fragments (Fig. 5B, E), suggesting that Gfap and Vim gene deletion did not alter APP expression or processing.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Cultured adult astrocytes can migrate to and degrade amyloid plaques in brain slices from aged APP transgenic mice.

    “In 2003, Wyss-Coray et al. (41) demonstrated that cultured adult astrocytes can migrate to and degrade amyloid plaques in brain slices from aged APP transgenic mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] 41. Wyss-Coray T., Loike J. D., Brionne T. C., Lu E., Anankov R., Yan F., Silverstein S. C., Husemann J. (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med. 9, 453–457 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Microglia can internalize and clear Aβ in vitro.

    “In vitro studies subsequently demonstrated that microglia can internalize and clear Aβ (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 8. Paresce D. M., Ghosh R. N., Maxfield F. R. (1996) Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor. Neuron 17, 553–565 [DOI] [PubMed] [Google Scholar] source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Near-complete ablation of microglia in APP/PS1 mice had no effect on plaque deposition or neuritic dystrophy.

    “However, near-complete ablation of microglia in transgenic mice expressing mutant human amyloid precursor protein (APP) and presenilin 1 (PS1) had no effect on plaque deposition or neuritic dystrophy (13), raising questions about the role of endogenous microglia in plaque clearance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 13. Grathwohl S. A., Kalin R. E., Bolmont T., Prokop S., Winkelmann G., Kaeser S. A., Odenthal J., Radde R., Eldh T., Gandy S., Aguzzi A., Staufenbiel M., Mathews P. M., Wolburg H., Heppner F. L., Jucker M. (2009) Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 [DOI] [PMC free article] [PubMed] [Google Scholar]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Gfap/Vim deletion does not alter expression or processing of APP or Aβ-degrading proteases.

    “Gfap/Vim deletion does not alter expression or processing of APP or Aβ-degrading proteases”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Microglia can engulf amyloid-β and sequester it in endosome-like compartments.

    “Early ultrastructural studies in human brain specimens suggested that microglia can engulf amyloid-β (Aβ) and sequester it in endosome-like compartments (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] 7. Frackowiak J., Wisniewski H. M., Wegiel J., Merz G. S., Iqbal K., Wang K. C. (1992) Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce β-amyloid fibrils. Acta Neuropathol. 84, 225–233 [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Gfap and Vim deletion selectively alters insoluble (plaque-associated) Aβ but not the soluble pools of Aβ in APP/PS1 mice.

    “These data suggest that Gfap and Vim deletion selectively alters insoluble (plaque-associated) Aβ but not the soluble pools of Aβ in APP/PS1 mice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § RESULTS

    APP transgenic mice do not show significant neuronal cell death or brain atrophy, in contrast to brains of patients with AD.

    “In general, APP transgenic mice do not show significant neuronal cell death or brain atrophy, in contrast to brains of patients with AD (49).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] 49. Irizarry M. C., McNamara M., Fedorchak K., Hsiao K., Hyman B. T. (1997) APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J. Neuropathol. Exp. Neurol. 56, 965–973 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § MATERIALS AND METHODS

    Mice of both genotypes were maintained on the same mixed backgrounds (B6C3 × C57BL 129SV 129Ola).

    “Mice of both genotypes were maintained on the same mixed backgrounds (B6C3 × C57BL 129SV 129Ola).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Activated astrocytes either protect neurons from developing dystrophic neurites or are involved in the clearance of dystrophic neurites.

    “These findings suggest that activated astrocytes either protect neurons from developing dystrophic neurites or are involved in the clearance of dystrophyic neurites.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Gfap and Vim deletion does not alter ISF Aβ levels or metabolism but selectively alters amyloid plaque load.

    “Thus, Gfap and Vim deletion does not alter ISF Aβ levels or metabolism but selectively alters amyloid plaque load.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § RESULTS

    Gfap/Vim deletion selectively affects astrocyte activation, an event that occurs after initial plaque formation.

    “These data suggest that Gfap and Vim deletions do not influence the initial deposition of plaques but exacerbate subsequent plaque accumulation, consistent with the contention that Gfap/Vim deletion selectively affects astrocyte activation—an event that occurs after initial plaque formation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In APP/PS1 mice, plaque accumulation begins at about 4 months of age and increases thereafter.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Gfap and Vim deletions do not influence the initial deposition of plaques but exacerbate subsequent plaque accumulation.

    “These data suggest that Gfap and Vim deletions do not influence the initial deposition of plaques but exacerbate subsequent plaque accumulation, consistent with the contention that Gfap/Vim deletion selectively affects astrocyte activation—an event that occurs after initial plaque formation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In APP/PS1 mice, plaque accumulation begins at about 4 months of age and increases thereafter.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Plaque-degrading activity in astrocytes is dependent on apolipoprotein E (apoE) expression.

    “Moreover, this plaque-degrading activity in astrocytes was subsequently found to be dependent on apolipoprotein E (apoE) expression (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] 42. Koistinaho M., Lin S., Wu X., Esterman M., Koger D., Hanson J., Higgs R., Liu F., Malkani S., Bales K. R., Paul S. M. (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat. Med. 10, 719–726 [DOI] [PubMed] [Google Scholar] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Aβ has been observed in vesicles within astrocytes.

    “and Aβ has been observed in vesicles within astrocytes (57, 58).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] 57. Yamaguchi H., Sugihara S., Ogawa A., Saido T. C., Ihara Y. (1998) Diffuse plaques associated with astroglial amyloid β-protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol. 95, 217–222 [DOI] [PubMed] [Google Scholar] source
    • cites [58] 58. Thal D. R., Schultz C., Dehghani F., Yamaguchi H., Braak H., Braak E. (2000) Amyloid β-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex. Acta Neuropathol. 100, 608–617 [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Interpretationown data
    § DISCUSSION

    The major change induced by Gfap and Vim gene deletion appeared to be morphology of activated astrocytes without any major transcriptional change identified.

    “Thus, the major change induced by Gfap and Vim gene deletion appeared to be morphology of activated astrocytes without any major transcriptional change identified.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § RESULTS

    BDNF may play a role in amyloid associated pathology.

    “and that this may play a role in amyloid associated pathology (52).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] 52. Szapacs M. E., Numis A. L., Andrews A. M. (2004) Late onset loss of hippocampal 5-HT and NE is accompanied by increases in BDNF protein expression in mice co-expressing mutant APP and PS1. Neurobiol. Dis. 16, 572–580 [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Interpretationreasoning
    § DISCUSSION

    Individual deletion of Gfap or Vim allows formation of intermediate filament networks and astrocyte activation under pathological conditions.

    “Thus, individual deletion of Gfap or Vim allows formation of intermediate filament networks and astrocyte activation under pathological conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Deletion of Gfap and Vim alters the activation and morphology of astrocytes without altering their viability.

    “suggesting that deletion of Gfap and Vim alters the activation and morphology of astrocytes without altering their viability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Astrocyte density (GFP-expressing or glutamine synthetase-immunostained) is a valid measure of astrocyte viability.

  • Classified as probably not a substantial claim.

    Premisecitation
    § DISCUSSION

    Near-complete ablation of microglia in APP mice does not alter plaque load.

    “Furthermore, near-complete ablation of microglia in APP mice does not alter plaque load (13).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 13. Grathwohl S. A., Kalin R. E., Bolmont T., Prokop S., Winkelmann G., Kaeser S. A., Odenthal J., Radde R., Eldh T., Gandy S., Aguzzi A., Staufenbiel M., Mathews P. M., Wolburg H., Heppner F. L., Jucker M. (2009) Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 [DOI] [PMC free article] [PubMed] [Google Scholar]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Astrocytes support neuronal function by regulating extracellular concentrations of ions and neurotransmitters, especially in response to cellular stress.

    “Astrocytes support neuronal function by regulating extracellular concentrations of ions and neurotransmitters (65), especially in response to cellular stress (21).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] 65. Allen N. J., Barres B. A. (2009) Neuroscience: Glia - more than just brain glue. Nature 457, 675–677 [DOI] [PubMed] [Google Scholar] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. source
    • cites [21] 21. Pekny M., Lane E. B. (2007) Intermediate filaments and stress. Exp. Cell Res. 313, 2244–2254 [DOI] [PubMed] [Google Scholar] source
50 of 50

  • The paper relies on this without support.

    Direct evidence that reactive gliosis suppresses plaque accumulation is lacking.

    “However, direct evidence that reactive gliosis suppresses plaque accumulation is lacking.”

  • The paper relies on this without support.

    In APP/PS1 mice, plaque accumulation begins at about 4 months of age and increases thereafter.

    “In APP/PS1 mice, plaque accumulation begins at ∼4 mo of age and increases thereafter.”

  • The paper relies on this without support.

    The role of reactive astrocytes in Alzheimer's disease pathogenesis is unclear.

    “Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear.”

  • The paper relies on this without support.

    With the exception of Batten's disease, the role of astrocyte intermediate filament proteins in chronic neurodegenerative diseases has not been investigated.

    “With the exception of Batten's disease (33), the role of astrocyte intermediate filament proteins in chronic neurodegenerative diseases has not been investigated.”

  • The paper relies on this without support.

    X-34 staining specifically and quantitatively identifies amyloid plaques.

    “Processes were also evident deep within X-34-stained plaques, suggesting process invasion within plaques (Fig. 6C).”

  • The paper relies on this without support.

    GFP expression driven by the Gfap promoter specifically labels astrocytes and reveals their complete morphology.

    “mice were injected with AAV2 constructs carrying GFP driven by a Gfap promoter (AAV-GFAP-GFP)”
    “we expressed GFP in astrocytes in vivo to observe the complete cellular profile of the cells”

  • The paper relies on this without support.

    Astrocyte density (GFP-expressing or glutamine synthetase-immunostained) is a valid measure of astrocyte viability.

    “suggesting that deletion of Gfap and Vim alters the activation and morphology of astrocytes without altering their viability.”

  • The paper relies on this without support.

    The increase in amyloid plaque load in APP/PS1 Gfap−/−Vim−/− mice is due to attenuated astrocyte activation rather than other effects of Gfap/Vim deletion.

    “In summary, our studies demonstrate that reactive gliosis around amyloid plaques is important for restricting the appearance and growth of amyloid plaques in APP mice.”

  • The paper relies on this without support.

    Microglial density and plaque overlap reflect microglial recruitment, proliferation, or function around plaques.

    “Thus, microglia seem to be more abundant around plaques in the absence of activated astrocytes.”

  • The paper relies on this without support.

    Gene expression levels measured by quantitative PCR reflect functional protein activity.

    “Quantitative PCR analysis revealed no difference in BDNF message levels (Supplemental Fig. S3G).”
    “Real-time PCR from the cortex of 12-mo-old mice confirmed an increased gene expression of CD11b and Iba-1 in APP/PS1 Gfap−/−Vim−/− mice”

  • The paper relies on this without support.

    The measured half-life of ISF Aβ is representative of Aβ metabolism relevant to plaque pathogenesis.

    “and the half-life of ISF Aβ was unchanged.”
11 of 11

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 consensus is that reduction in astrocyte density leads to higher amyloid levels, without changes in its aggregation or deposition.

    “Therefore, it seems that the consensus is that the reduction in astrocyte density leads to higher amyloid levels, without changes in its aggregation or deposition.”

    From Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease (2021) · cites this paper as [29]

    The Results (Fig. 6E) found no significant difference in astrocyte density between genotypes; the deletions altered astrocyte activation and morphology instead. The Discussion reports increased plaque burden in the mice with attenuated astrocyte activation and concludes that reactive gliosis restricts plaque appearance and growth. Both points run contrary to the claimed reduction in density without a change in deposition. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Our astrocyte population in the CNO group did not show the transcriptional profile of reactive astrogliosis typically seen in neurodegenerative diseases.

    “We also observed that our astrocyte population in the CNO group did not show the transcriptional profile of reactive astrogliosis that is typically seen in neurodegenerative diseases (Supplementary Figure 2D) (Kraft et al., 2013).”

    From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Kraft et al., 2013

    The introductory passage (labeled Abstract in our copy; page unavailable) describes reactive astrocytes as showing increased GFAP and vimentin, and the Results describe their characteristic process hypertrophy in APP/PS1 mice. These passages support a general description of reactive astrogliosis, but do not establish a broader transcriptional profile typical of neurodegenerative diseases. The CNO-group observation is the citing authors’ own result, not a finding attributed to Kraft et al. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • GFAP knockout results in an increase in Aβ load, implicating GFAP as required for astrocyte activation in response to AD pathology.

    “It has been demonstrated that GFAP knockout results in an increase in A β load, thereby implicating the filament protein that is required for astrocyte activation in the response to AD pathology (Kraft et al., 2013).”

    From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Kraft et al., 2013

    The Abstract reports increased plaque load in APP/PS1 mice after deletion of both Gfap and Vim, not Gfap alone. The Discussion states that deleting either gene individually still allows astrocyte activation under pathological conditions, so the paper does not establish that GFAP alone is required for that response. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Reactive astrocytes have been reported to phagocytose and degrade Aβ, reducing Aβ plaque burden in the brain.

    “reactive astrocytes have been reported to phagocytose and degrade Aβ, reducing Aβ plaque burden in the brain (Wyss-Coray et al., 2003;Koistinaho et al., 2004;Kraft et al., 2013;Gomez-Arboledas et al., 2018;Preman et al., 2021)”

    From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Kraft et al., 2013

    The Discussion reports that reactive gliosis restricts plaque appearance and growth in APP mice. It also says that phagocytosis of plaque material by astrocytes is possible but that direct evidence is lacking; the mechanism of the plaque-suppressing effect remains unclear. Thus the source supports reduced plaque burden, but not the claim that phagocytosis and degradation are the established means by which reactive astrocytes achieve it. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Astrocytes can modulate microglial responses to Aβ.

    “Moreover, astrocytes can also modulate microglial responses to Aβ [55, 58, 59].”

    From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [55]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • MMP-9 expression is described as both changed and unchanged

    Minor

    The results report a significant decrease in MMP-9 mRNA, an Aβ-degrading protease measured in the study. The discussion later says no significant differences were found in the expression of Aβ-degrading proteases, without limiting that statement to protein levels.

1 of 1

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Authors
Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., & Lee, J.
Affiliations
  • Washington University in St. Louis (US)
  • University of Gothenburg (SE)
Corresponding author
Lee, Jin‐Moo
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2012-10-04
Volume
27
Issue
1
Pages
187-198
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.12-208660
PMC
PMC3528309
OpenAlex
W2164490896
Semantic Scholar
459fcf0772019eda0ac89ec7c2f7f0ff9d4dbe73
Cited by
324
References
69
Citations by year
2026: 20 · 2025: 23 · 2024: 24 · 2023: 17 · 2022: 21 · 2021: 25 · 2020: 25 · 2019: 30 · 2018: 27 · 2017: 21 · 2016: 19 · 2015: 30 · 2014: 28 · 2013: 14
FWCI
13.58
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (R01 NS48283, R01 NS67905, P01 NS32636, R37 AG13956, P30NS69329)
  • Medicinska Forskningsrådet (11548)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
astrocyte activation, amyloid plaques, Alzheimer's disease, amyloid-beta, APP/PS1 mice, glial fibrillary acidic protein, vimentin, intermediate filaments, dystrophic neurites, astrocyte morphology, plaque progression
MeSH terms
Animals, Astrocytes, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Blotting, Western, Amyloid beta-Protein Precursor, Mice, Presenilin-1, Real-Time Polymerase Chain Reaction

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

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