Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice

In the paper

“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).”

What the sources say

• Supported

  The Abstract (p. 1590) reports that mice lacking GFAP developed and reproduced normally, with no detected abnormalities across the functions examined. This supports the GFAP-deficient case in the claim; this paper does not itself test mice lacking vimentin. (LLM, conf=0.92)

  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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [21] 21. Pekny M., Lane E. B. (2007) Intermediate filaments and stress. Exp. Cell Res. 313, 2244–2254 [DOI] [PubMed] [Google Scholar] source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [15] 15. Pekny M., Nilsson M. (2005) Astrocyte activation and reactive gliosis. Glia 50, 427–434 [DOI] [PubMed] [Google Scholar] source
• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Supported

  Citation (6) is attached to the interferon-γ example, not the lipopolysaccharide or interleukin-6 examples. The Discussion reports that interferon-γ expression produced glial activation and reduced amyloid-β deposition in APP transgenic mice; the Results quantify plaque-burden reductions of 70–73% in one experimental paradigm. (LLM, conf=0.94)

  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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  The Discussion reports that disease progressed faster in GFAP−/−Vim−/−PPT1−/− mice than in PPT1−/− mice and describes the GFAP/vimentin deficiency as a model of attenuated astrocyte activation. Citation 33 supports the Batten’s-disease portion of the sentence; the focal-ischemia finding is assigned to citation 32. (LLM, conf=0.93)

  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

In the paper

“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).”

What the sources say

• Supported

  This source is cited for the synapse-regeneration portion of the sentence, not the separately cited claims about axons, neurogenesis, or spinal-cord recovery. The Results report that after entorhinal cortex lesion, synaptic complexes increased by 77% in Gfap−/−Vim−/− mice between days 4 and 14, compared with 11% in wild-type mice. (LLM, conf=0.94)

  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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  Citation (38) attaches to the hippocampal transplantation finding, not the retinal-graft finding cited as (37). The Introduction says the study compared neurons and astrocytes differentiated from grafted neural progenitor cells, and the Abstract reports more transplant-derived neurons and astrocytes in GFAP−/−Vim−/− mice than in wild-type controls 35 days after transplantation. The supplied passages do not give page numbers. (LLM, conf=0.93)

  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

In the paper

“However, after brain or spinal cord injury, reactive gliosis and the formation of glial scar are attenuated and the healing process is prolonged (22).”

What the sources say

• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• Supported

  The Introduction (page unavailable) identifies GFAP, vimentin, synemin and nestin as astrocyte intermediate-filament proteins and states that synemin cannot assemble into filaments on its own, resembling nestin. The Discussion (page unavailable) reports no detectable synemin in Gfap−/−Vim−/− reactive astrocytes and markedly reduced nestin. Together, these passages support the explanation that nestin and synemin cannot form filaments in the double-knockout astrocytes. (LLM, conf=0.87)

  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

In the paper

“On a cellular level, astrocytes of Gfap−/−Vim−/− mice in the injured area do not develop the characteristic hypertrophy of proximal processes (23).”

What the sources say

• Supported

  The Figure 1 caption states that, after entorhinal cortex lesion, wild-type astrocytic processes became hypertrophic whereas those in GFAP−/− Vim−/− mice did not. The Results (Fig. 1) also report shorter reactive astrocytic processes on the lesioned side in the double-knockout mice. (LLM, conf=0.93)

  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

In the paper

“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).”

What the sources say

• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• Supported

  In the Abstract, the authors report that microglia were attracted to newly formed plaques within a day in APP transgenic mice. They also suggest that microglia may restrict plaque growth, matching the claim’s qualified wording. (LLM, conf=0.93)

  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
• Supported

  The Abstract reports that microglia migrate toward plaques in transgenic mice and that changes in plaque size are related to the volume of associated microglia. The Microglial migration section describes cells moving to plaque peripheries over 24–48 hours. The claim's cautious wording, “may alter,” is consistent with these findings. (LLM, conf=0.93)

  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

In the paper

“But when Gfap and Vim are both deleted, astrocytes cannot form intermediate filament networks or display reactive morphology (22, 23, 32).”

What the sources say

• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

What the sources say

• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• Supported

  This paper supplies one of the injury models covered by the sentence’s multiple citations. In the entorhinal cortex lesion model, Figure 1 reports that GFAP/Vim-deficient mice did not develop the astrocytic process hypertrophy seen in wild-type mice (pp. 5016–5021). (LLM, conf=0.91)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Previous work has shown BDNF expression is increased in amyloid-associated astrocytes (51)”

What the sources say

• Supported

  The section on plaque-associated astroglial and microglial cells reports numerous BDNF-positive astrocytes around amyloid plaques, while astroglial cells in plaque-free areas were BDNF-negative. This supports increased BDNF expression in amyloid-associated astrocytes in the APP23 mouse model studied. (LLM, conf=0.92)

  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

In the paper

“and that MMP-9 is capable of degrading amyloid fibrils in vitro and amyloid plaques in situ (61).”

What the sources say

• Supported

  The paper reports that MMP-9 degrades amyloid-β fibrils in vitro. Its Discussion also states that MMP-9 degrades compact amyloid plaques in brain sections from aged APP/PS1 mice, supporting the in situ part of the claim. (LLM, conf=0.94)

  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

In the paper

“Under baseline conditions, however, Gfap−/−Vim−/− mice have astrocytes of normal appearance and grossly normal brain anatomy (22, 23, 32).”

What the sources say

• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“The intermediate filament proteins GFAP and Vim are expressed at high levels in activated astrocytes and are critical for the activated phenotype.”

What the sources say

• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“Astrocyte endfeet line the abluminal aspect of endothelial cells and are important for the formation and maintenance of the blood-brain-barrier (29).”

What the sources say

• ?Could not verify

  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)

  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] sourceExperimental — accuracy not yet measured

In the paper

“Although microglia can internalize fibrillar Aβ in vitro and in vivo”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured

In the paper

“Moreover, astrocytes may play an important role in the transport of Aβ into or out of the CNS through this important interface (63).”

What the sources say

• Partly supported

  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)

  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] sourceExperimental — accuracy not yet measured

In the paper

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

In the paper

“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”

In the paper

“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).”

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“ApoE and apoJ (clusterin) showed no significant differences (Fig. 5C, E).”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“In vitro studies subsequently demonstrated that microglia can internalize and clear Aβ (8).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not matched

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

In the paper

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

In the paper

“Early ultrastructural studies in human brain specimens suggested that microglia can engulf amyloid-β (Aβ) and sequester it in endosome-like compartments (7).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“In general, APP transgenic mice do not show significant neuronal cell death or brain atrophy, in contrast to brains of patients with AD (49).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“Moreover, this plaque-degrading activity in astrocytes was subsequently found to be dependent on apolipoprotein E (apoE) expression (42).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“and Aβ has been observed in vesicles within astrocytes (57, 58).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“and that this may play a role in amyloid associated pathology (52).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

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

In the paper

“Furthermore, near-complete ablation of microglia in APP mice does not alter plaque load (13).”

What the sources say

• ?Not matched

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

In the paper

“Astrocytes support neuronal function by regulating extracellular concentrations of ions and neurotransmitters (65), especially in response to cellular stress (21).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [21] 21. Pekny M., Lane E. B. (2007) Intermediate filaments and stress. Exp. Cell Res. 313, 2244–2254 [DOI] [PubMed] [Google Scholar] source