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Cited by 55Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease

Open access
Satoh, Jun-ichi, Kino, Yoshihiro, Yanaizu, Motoaki, Tosaki, Youhei, Sakai, Kenji, Ishida, Tsuyoshi, Saito, Yuko·2017·Intractable & Rare Diseases Research
DOI 10.5582/irdr.2017.01073PMC PMC5735279
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Abstract

Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2 expressed in microglia. A rare variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD). A recent study demonstrated that a rare coding variant p.Ser209Phe in the ABI family member 3 (ABI3) gene, a regulator of actin cytoskeleton organization, confers risk of developing of LOAD, although the pattern of ABI3 expression in AD and NHD brains with relevance to microglial pathology remains to be characterized. We investigated the cell type-specific expression of ABI3 in the brains derived from four non-neurological controls (NC), ten AD and five NHD cases by immunohistochemistry. We identified an intense ABI3 immunoreactivity chiefly on a subset of microglia with ramified or amoeboid morphology located in the grey matter and the white matter of the frontal cortex and the hippocampus of NC, AD, and NHD cases. The immunolabeled area of ABI3-positive microglia was not significantly different among NC, AD, and NHD cases due to great variability from case to case. The clusters of ABI3-immunoreactive microglia were found exclusively in AD brains and they were associated with amyloid plaques. Although these observations do not actively support the view that ABI3-immunoreactive microglia play a central role in the development of leukoencephalopathy in NHD brains and the neurodegeneration in AD brains, the intense expression of ABI3 on microglia might regulate their migration under conditions of health and disease in the central nervous system (CNS).

AI snapshot

Written from the paper’s full text.

TL;DR

ABI3 immunoreactivity was found chiefly on a subset of microglia in non-neurological control, Alzheimer's disease (AD), and Nasu-Hakola disease (NHD) brains. Clusters of ABI3-immunoreactive microglia were found exclusively in AD brains and were associated with amyloid plaques, but the biological implications remain unclear.

Key findings

  • Intense ABI3 immunoreactivity was localized chiefly to a subset of microglia with ramified or amoeboid morphology in grey and white matter of frontal cortex and hippocampus from NC, AD, and NHD cases; double labeling showed overlap with gp91phox but not GFAP-positive astrocytes, CNPase-positive oligodendrocytes, or NeuN-positive neurons.
  • The ABI3-immunolabeled area of microglia did not differ significantly among NC, AD, and NHD cases in grey matter (p = 0.8689) or white matter (p = 0.8237), with great case-to-case variability.
  • Clusters of ABI3-immunoreactive microglia were found exclusively in AD brains and were often closely associated with amyloid plaques; such clusters were almost undetectable in NC and NHD brains.
  • In HMO6 human microglial cells, TGFβ1 treatment significantly elevated ABI3 mRNA expression (p = 0.0001), whereas LPS, IFNγ, IL-4, or IL-13 did not.

Methods

  • Immunohistochemistry was performed on serial sections of frontal cortex and hippocampus from four non-neurological controls, ten AD patients, and five NHD patients, using anti-ABI3 antibody HPA017345 validated by western blot of recombinant human ABI3.
  • Double immunolabeling used antibodies against ABI3 plus GFAP, NeuN, CNPase, gp91phox, or amyloid-β; ABI3-immunolabeled area was quantified with ImageJ and calibrated to Iba1-immunolabeled area, with differences among groups tested by one-way ANOVA followed by Tukey's test.
  • Quantitative RT-PCR measured ABI3 mRNA in HMO6 microglial cells after 24-hour exposure to LPS, IFNγ, IL-4, IL-13, or TGFβ1, standardized to G3PDH.

Limitations

  • The paper states that the biological implications of intense ABI3 expression on microglia in AD and NHD brains remain to be clarified, and that the observations do not actively support a central role for ABI3-immunoreactive microglia in NHD leukoencephalopathy or AD neurodegeneration.
  • The text makes evident that the sample was small (4 NC, 10 AD, 5 NHD) and that ABI3 immunolabeling varied greatly from case to case, limiting statistical power.
  • The text also makes evident that genetic analysis was not performed in NHD3 or NHD4, and that the functional studies used only the HMO6 microglial cell line.

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

Integrity signals

Registry

Crossref · 10.5582/irdr.2017.01073

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 32 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    ABI3 expression pattern overlapped with that of gp91phox, a marker of microglia.

    “By double immunolabeling, the expression pattern of ABI3 overlapped with that of gp91phox, a marker of microglia (15) (Figure 5, panel a), whereas GFAP-positive astrocytes, CNPase-positive oligodendrocytes, and NeuN-positive neurons did not express ABI3 (Figure 5, panels b-d), suggesting that astrocytes, oligodendrocytes and neurons do not express discernible levels of ABI3”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] 15. Satoh JI, Kino Y, Yanaizu M, Tosaki Y, Sakai K, Ishida T, Saito Y. Expression of gp91phox and p22phox, catalytic subunits of NADPH oxidase, on microglia in Nasu-Hakola disease brains. Intractable Rare Dis Res. 2016; 5:275-279. source
  • Premisecitation

    Microglia, along with macrophages, are capable of producing podosomes, a matrix-degrading ventral cell surface structure similar to invadopodia.

    “Microglia, along with macrophages, are capable of producing podosomes, a matrix-degrading ventral cell surface structure similar to invadopodia (24).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] 24. Vincent C, Siddiqui TA, Schlichter LC. Podosomes in migrating microglia: Components and matrix degradation. J Neuroinflammation. 2012; 9:190. source
  • Findingown data

    The homozygous mutation of a single base deletion of 141G (c.141delG) in exon 3 of DAP12 was identified in NHD1, NHD2, and NHD5.

    “The homozygous mutation of a single base deletion of 141G (c.141delG) in exon 3 of DAP12 was identified in NHD1, NHD2, and NHD5, while the genetic analysis was not performed in NHD3 or NHD4.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The clusters of ABI3-expressing microglia were almost undetectable in both NC and NHD brains.

    “In contrast, the clusters of ABI3-expressing microglia were almost undetectable in both NC and NHD brains.”
    Quote in the paperSubstantial claim
  • Findingown data

    ABI3 immunoreactivity is chiefly on a subset of microglia with ramified or amoeboid morphology located in the grey matter and the white matter of the frontal cortex and the hippocampus of NC, AD, and NHD cases.

    “We identified an intense ABI3 immunoreactivity chiefly on a subset of microglia with ramified or amoeboid morphology located in the grey matter and the white matter of the frontal cortex and the hippocampus of NC, AD, and NHD cases.”
    • Also stated in: § 3. Results · plain
      “Then, by immunohistochemistry using HPA017345, we identified an intense expression of ABI3 immunoreactivity chiefly on a subset of microglia with ramified or amoeboid morphology located in the grey matter and the white matter of the frontal cortex and the hippocampus derived from NC, AD, and NHD subjects (Figures 234, panels a-d).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 15

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

    Premisecitation

    Forced expression of ABI3 in thyroid cancer cells substantially reduced the phosphorylation of AKT at both Thr308 and Ser473 and GSK3β at Ser9.

    “Forced expression of ABI3 in thyroid cancer cells substantially reduced the phosphorylation of AKT at both Thr308 and Ser473 and GSK3β at Ser9 (26).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] 26. Moraes L, Zanchin NIT, Cerutti JM. ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway. Oncotarget. 2017; 8:67769-67781. source

  • May combine two claims.

    Premisecitation

    ABI3 mRNA expression is upregulated in TREM2-deficient microglia that exhibit a reduction in chemotaxis and migration.

    “In contrast, ABI3 mRNA expression is upregulated in TREM2-deficient microglia that exhibit a reduction in chemotaxis and migration (25).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] 25. Mazaheri F, Snaidero N, Kleinberger G, et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 2017; 18:1186-1198. source

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

    Premisecitation

    Non-phosphorylated form of ABI3 is preferentially incorporated in WRC, while the phosphorylated form represents an inactive protein not included in the complex.

    “Non-phosphorylated form of ABI3 is preferentially incorporated in WRC, while the phosphorylated form represents an inactive protein not included in the complex.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] 26. Moraes L, Zanchin NIT, Cerutti JM. ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway. Oncotarget. 2017; 8:67769-67781. source

      The Results ('WAVE 2 and CYFIP1 are ABI3-interacting proteins') report that non-phosphorylated ABI3 preferentially co-precipitated with WAVE2. They say only that phosphorylation *may* generate an inactive form unable to interact with WAVE2; the Discussion likewise presents inhibition of WRC formation as a proposed model. The claim overstates that proposed interpretation as an established fact. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    ABI3 serves as a downstream mediator of the PI3K/AKT pathway that disrupts WRC via phosphorylation of ABI3.

    “ABI3 serves as a downstream mediator of the PI3K/AKT pathway that disrupts WRC via phosphorylation of ABI3 (26).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] 26. Moraes L, Zanchin NIT, Cerutti JM. ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway. Oncotarget. 2017; 8:67769-67781. source

      The Discussion proposes that PI3K/AKT signaling controls ABI3 phosphorylation and that phosphorylated ABI3 inhibits WRC formation. It presents this as a suggested model, however, rather than establishing the unqualified mechanism stated in the citing sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    ABI3 is phosphorylated at Ser342 by signaling through the PI3K/AKT pathway.

    “ABI3 is phosphorylated at Ser342 by signaling through the PI3K/AKT pathway.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] 26. Moraes L, Zanchin NIT, Cerutti JM. ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway. Oncotarget. 2017; 8:67769-67781. source

      The Results section reports that the S342A mutation and PI3K/AKT inhibition shift ABI3 toward its non-phosphorylated form. The Discussion interprets this as suggesting that PI3K/AKT potentially phosphorylates ABI3 at S342; it does not establish the claim's unqualified pathway attribution, and the Results note that another pathway might phosphorylate S342 in one cell line. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    AD is characterized by the hallmark pathology comprised of widespread amyloid-β (Aβ) deposition, neurofibrillary tangle (NFT) formation, extensive neurodegeneration, and profound activation of microglia in the brain.

    “Alzheimer's disease (AD) is characterized by the hallmark pathology comprised of widespread amyloid-β (Aβ) deposition, neurofibrillary tangle (NFT) formation, extensive neurodegeneration, and profound activation of microglia in the brain (6).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] 6. Sarlus H, Heneka MT. Microglia in Alzheimer's disease. J Clin Invest. 2017; 127:3240-3249. source

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

    Premisecitation

    WRC containing ABI3 is functionally distinct from that containing ABI1.

    “WRC containing ABI3 is functionally distinct from that containing ABI1 (17,18).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] 17. Hirao N, Sato S, Gotoh T, Maruoka M, Suzuki J, Matsuda S, Shishido T, Tani K. NESH (Abi-3) is present in the Abi/WAVE complex but does not promote c-Abl-mediated phosphorylation. FEBS Lett. 2006; 580:6464-6470. source

      The Introduction reports that ABI1 promotes c-Abl-mediated phosphorylation of Mena and WAVE2 whereas ABI3 does not, and that both participate in the Abi/WAVE complex. The Discussion says it is *possible* that complexes containing them differ in regulation by c-Abl; it does not establish the broader, unqualified claim that the complexes are functionally distinct. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] 18. Sekino S, Kashiwagi Y, Kanazawa H, Takada K, Baba T, Sato S, Inoue H, Kojima M, Tani K. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun Signal. 2015; 13:41. source

  • Classified as probably not a substantial claim.

    Premisecitation

    A rare coding variant p.Ser209Phe in the ABI3 gene confers risk of developing LOAD.

    “A recent study demonstrated that a rare coding variant p.Ser209Phe in the ABI family member 3 (ABI3) gene, a regulator of actin cytoskeleton organization, confers risk of developing of LOAD, although the pattern of ABI3 expression in AD and NHD brains with relevance to microglial pathology remains to be characterized.”
    • Also stated in: § 1. Introduction · plain
      “They are composed of a protective variant of p.Pro522Arg in PLCG2, a risk variant of p.Ser209Phe in ABI3, and a risk variant of p.Arg62His in TREM2.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] 11. Sims R, van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017; 49:1373-1384. source

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

    Study design and conductcitation

    AD cases were categorized into stage C of amyloid deposition and stage VI of neurofibrillary degeneration, following Braak's staging.

    “They were categorized into the stage C of amyloid deposition and the stage VI of neurofibrillary degeneration, following the Braak's staging (13).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] 13. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006; 112:389-404. source

      The staging system section defines six stages of AD-related neurofibrillary pathology, and its description of stage VI supports the cited basis for that classification. The passages do not describe a stage C of amyloid deposition or establish how the citing paper’s cases were categorized. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A rare variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD).

    “A rare variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD).”
    • Also stated in: § 1. Introduction · plain
      “The most notable example is a significant association between an approximately 3-fold increase in the risk for LOAD and a rare variant of the TREM2 gene encoding p.Arg47His located in the ligand binding domain of TREM2 (10).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] 10. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013; 368:107-116. source

      The Results (Association of Variant with Alzheimer’s Disease; page not supplied) identify the rare TREM2 R47H variant and report an odds ratio of 2.92, approximately threefold. The paper establishes an association, however, and its Conclusions describe a possible mechanism rather than demonstrating that the variant causes the increase in risk. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Both ABI1 and ABI2 but not ABI3 promote the c-ABL-mediated phosphorylation of WAVE2, since ABI3 does not directly interact with c-ABL.

    “Both ABI1 and ABI2 but not ABI3 promote the c-ABL-mediated phosphorylation of WAVE2, since ABI3 does not directly interact with c-ABL (17,18).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] 17. Hirao N, Sato S, Gotoh T, Maruoka M, Suzuki J, Matsuda S, Shishido T, Tani K. NESH (Abi-3) is present in the Abi/WAVE complex but does not promote c-Abl-mediated phosphorylation. FEBS Lett. 2006; 580:6464-6470. source

      Section 3.1 reports that Abi-1 and Abi-2 promoted c-Abl-mediated WAVE2 phosphorylation, whereas NESH (Abi-3) did not. Sections 3.2 and 4 say NESH was not detected interacting with c-Abl in the assay and that reduced or absent binding is the most likely explanation; they do not establish that it cannot interact directly or that this explanation is certain. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [18] 18. Sekino S, Kashiwagi Y, Kanazawa H, Takada K, Baba T, Sato S, Inoue H, Kojima M, Tani K. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun Signal. 2015; 13:41. source

      The Discussion reports that ABI1, but not ABI3, promotes c-ABL-mediated WAVE2 phosphorylation; the Abstract Background says ABI3 does not bind c-ABL. The Background describes ABI2 only as a *possible* mediator of this signaling, so the claim that ABI2 promotes WAVE2 phosphorylation is stronger than this paper supports. No page numbers are available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Microglia is lost in the CNS-specific TGFβ1 deficient mice that exhibit progressive motor paralysis and death by 23-25 weeks of age, indicating that TGFβ1 acts as a major differentiation and survival factor for microglia.

    “Microglia is lost in the CNSspecific TGFβ1 deficient mice that exhibit progressive motor paralysis and death by 23-25 weeks of age, indicating that TGFβ1 acts as a major differentiation and survival factor for microglia (28).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] 28. Butovsky O, Jedrychowski MP, Moore CS, et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2014; 17:131-143. source

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

    Premisecitation

    Forced expression of ABI3 in v-src-transformed NIH3T3 (SRD) cells, thyroid cancer cells, or colon cancer cells inhibits cell growth, invasiveness and migration, and enhances cellular senescence in vitro and reduces the tumor growth and metastasis in vivo, indicating that ABI3 acts as a tumor suppressor gene.

    “Forced expression of ABI3 in v-src-transformed NIH3T3 (SRD) cells, thyroid cancer cells, or colon cancer cells inhibits cell growth, invasiveness and migration, and enhances cellular senescence in vitro and reduces the tumor growth and metastasis in vivo, indicating that ABI3 acts as a tumor suppressor gene (20,22).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [20] 20. Ichigotani Y, Yokozaki S, Fukuda Y, Hamaguchi M, Matsuda S. Forced expression of NESH suppresses motility and metastatic dissemination of malignant cells. Cancer Res. 2002; 62:2215-2219.
    • cites [22] 22. Latini FR, Hemerly JP, Freitas BC, Oler G, Riggins GJ, Cerutti JM. ABI3 ectopic expression reduces in vitro and in vivo cell growth properties while inducing senescence. BMC Cancer. 2011; 11:11. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    TGFβ1 plays a pivotal role in development and maintenance of microglia both in vitro and in vivo.

    “TGFβ1 plays a pivotal role in development and maintenance of microglia both in vitro and in vivo (28).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] 28. Butovsky O, Jedrychowski MP, Moore CS, et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2014; 17:131-143. source

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

    Premisecitation

    Microglia, resident myeloid cells in the central nervous system (CNS), play a pivotal role in maintenance of brain homeostasis, along with progression of neurodegenerative diseases.

    “Microglia, resident myeloid cells in the central nervous system (CNS), play a pivotal role in maintenance of brain homeostasis, along with progression of neurodegenerative diseases (7).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] 7. Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017; 35:441-468. source

  • May combine two claims.

    Premisecitation

    Treatment of SRD cells overexpressing ABI3 with a tyrosine kinase inhibitor imatinib mesylate markedly promotes formation of invadopodia and enhances the metastatic potential.

    “In contrast, treatment of SRD cells overexpressing ABI3 with a tyrosine kinase inhibitor imatinib mesylate markedly promotes formation of invadopodia, actin-rich ventral membrane protrusions with extracellular matrix-degrading activity, and enhances the metastatic potential (18,23).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [18] 18. Sekino S, Kashiwagi Y, Kanazawa H, Takada K, Baba T, Sato S, Inoue H, Kojima M, Tani K. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun Signal. 2015; 13:41. source
    • cites [23] 23. Matsuda S, Ichigotani Y, Okumura N, Yoshida H, Kajiya Y, Kitagishi Y, Shirafuji N. NESH protein expression switches to the adverse effect of imatinib mesylate. Mol Oncol. 2008; 2:16-19. source

      The study description and Figure 1 caption report that imatinib-treated NESH/SRD cells produced significantly more lung tumor nodules than controls, supporting enhanced metastatic potential. The passages retrieved do not report increased invadopodia formation or establish that the protrusions described in the citing sentence were observed in these cells (section labeled Abstract and Figure 1 caption; page numbers unavailable). (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    ABI3 is a regulator of actin cytoskeleton organization.

    “A recent study demonstrated that a rare coding variant p.Ser209Phe in the ABI family member 3 (ABI3) gene, a regulator of actin cytoskeleton organization, confers risk of developing of LOAD, although the pattern of ABI3 expression in AD and NHD brains with relevance to microglial pathology remains to be characterized.”
    • Also stated in: § 4. Discussion · plain
      “They constitute the WAVE regulatory complex (WRC) that regulates actin cytoskeleton organization (17,18).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] 17. Hirao N, Sato S, Gotoh T, Maruoka M, Suzuki J, Matsuda S, Shishido T, Tani K. NESH (Abi-3) is present in the Abi/WAVE complex but does not promote c-Abl-mediated phosphorylation. FEBS Lett. 2006; 580:6464-6470. source

      The Introduction identifies ABI3 as NESH and says its involvement in regulating the cellular cytoskeleton is suggested, while its mechanism remains unclear. The paper also shows that NESH belongs to the actin-regulating Abi/WAVE complex, but it does not establish ABI3 itself as a regulator of actin cytoskeleton organization as definitively as the citing sentence states. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [18] 18. Sekino S, Kashiwagi Y, Kanazawa H, Takada K, Baba T, Sato S, Inoue H, Kojima M, Tani K. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun Signal. 2015; 13:41. source

  • May combine two claims.

    Findingown data

    GFAP-positive astrocytes, CNPase-positive oligodendrocytes, and NeuN-positive neurons did not express ABI3.

    “By double immunolabeling, the expression pattern of ABI3 overlapped with that of gp91phox, a marker of microglia (15) (Figure 5, panel a), whereas GFAP-positive astrocytes, CNPase-positive oligodendrocytes, and NeuN-positive neurons did not express ABI3 (Figure 5, panels b-d), suggesting that astrocytes, oligodendrocytes and neurons do not express discernible levels of ABI3”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In AD brains, some ABI3-immunoreactive microglia formed clusters and were often closely associated with amyloid deposition.

    “The clusters of ABI3-immunoreactive microglia were found exclusively in AD brains and they were associated with amyloid plaques.”
    • Also stated in: § 3. Results · plain
      “In AD brains, some of ABI3-immunoreactive microglia formed the clusters and they were often closely associated with amyloid deposition (Figure 3, panels c, d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The immunolabeled area of ABI3-positive microglia was not significantly different among NC, AD, and NHD cases in the grey matter (p = 0.8689) and the white matter (p = 0.8237).

    “The immunolabeled area of ABI3-positive microglia was not significantly different among NC, AD, and NHD cases due to great variability from case to case.”
    • Also stated in: § 2.4. Quantitative RT-PCR analysis · plain
      “By quantitative analysis, the immunolabeled area of ABI3-positive microglia was not significantly different among NC, AD, and NHD cases in the grey matter (p = 0.8689) and the white matter (p = 0.8237) due to great variability in the area of ABI3immunolabeled microglia from case to case (Figure 6).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Microglia adopt two distinct activation phenotypes, composed of a proinflammatory and neurotoxic classical activation (M1) phenotype by exposure to LPS and IFNγ and an anti-inflammatory and neuroprotective alternative activation (M2) phenotype following treatment with IL-4 and IL-13.

    “Microglia adopt two distinct activation phenotypes, composed of a proinflammatory and neurotoxic”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] 27. Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 2016; 53:1181-1194. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2 expressed in microglia.

    “Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2 expressed in microglia.”
    • Also stated in: § 1. Introduction · plain
      “Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; OMIM 221770), is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either TYROBP(DAP12) or TREM2 (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] 1. Klünemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, De Bleecker JL, Rossor MN, Marienhagen J, Klein HE, Peltonen L, Paloneva J. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology. 2005; 64:1502-1507. source

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

    Study design and conductnone given

    The expression levels of ABI3 were standardized against the levels of glyceraldehyde-3-phosphate dehydrogenase (G3PDH) detected in the corresponding cDNA samples.

    “The expression levels of ABI3 were standardized against the levels of glyceraldehyde-3-phosphate dehydrogenase (G3PDH) detected in the corresponding cDNA samples.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Negative controls underwent all the steps except for exposure to primary antibody.

    “Negative controls underwent all the steps except for exposure to primary antibody.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A battery of genes, such as TREM2, BIN1, ABCA7, PICALM, CASS4, HLA-DRB1, MS4A6A, ZCWPW1, INPP5D and CD33, whose polymorphic variants modulate the risk of late-onset AD (LOAD), are expressed abundantly in microglia.

    “A battery of the genes, such as TREM2, BIN1, ABCA7, PICALM, CASS4, HLA-DRB1, MS4A6A, ZCWPW1, INPP5D and CD33, whose polymorphic variants modulate the risk of late-onset AD (LOAD), are expressed abundantly in microglia (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] 9. Yeh FL, Hansen DV, Sheng M. TREM2, microglia, and neurodegenerative diseases. Trends Mol Med. 2017; 23:512-533. source

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

    Premisecitation

    TGFβ1 promotes microglial clearance of amyloid-β.

    “Importantly, TGFβ1 promotes microglial clearance of amyloid-β (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] 30. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L. TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nat Med. 2001; 7:612-618. source

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

    Study design and conductown data

    The genetic analysis was not performed in NHD3 or NHD4.

    “The homozygous mutation of a single base deletion of 141G (c.141delG) in exon 3 of DAP12 was identified in NHD1, NHD2, and NHD5, while the genetic analysis was not performed in NHD3 or NHD4.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    TGFβ1-treated microglia show a quiescent phenotype that resembles M0 cells.

    “TGFβ1-treated microglia show a quiescent phenotype that resembles M0 cells (29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] 29. Abutbul S, Shapiro J, Szaingurten-Solodkin I, Levy N, Carmy Y, Baron R, Jung S, Monsonego A. TGF-β signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia. 2012; 60:1160-1171. source

  • May combine two claims.

    Interpretationown data

    Astrocytes, oligodendrocytes and neurons do not express discernible levels of ABI3.

    “By double immunolabeling, the expression pattern of ABI3 overlapped with that of gp91phox, a marker of microglia (15) (Figure 5, panel a), whereas GFAP-positive astrocytes, CNPase-positive oligodendrocytes, and NeuN-positive neurons did not express ABI3 (Figure 5, panels b-d), suggesting that astrocytes, oligodendrocytes and neurons do not express discernible levels of ABI3”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    A partial loss of function of the TREM2-DAP12 signaling pathway in microglia causes amyloid pathology, tau pathology, and neurodegeneration in AD.

    “These observations suggest that a partial loss of function of the TREM2-DAP12 signaling pathway in microglia causes amyloid pathology, tau pathology, and neurodegeneration in AD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The ABI3-immunolabeled area was calibrated by the Iba1-immunolabeled area.

    “The ABI3-immunolabeled area was calibrated by the Iba1-immunolabeled area.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The intense expression of ABI3 on microglia might regulate their migration under conditions of health and disease in the central nervous system (CNS).

    “the intense expression of ABI3 on microglia might regulate their migration under conditions of health and disease in the central nervous system (CNS).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    NHD is a primary disease of microglia termed microgliopathy.

    “Thus, NHD is a primary disease of microglia termed”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] 5. Satoh J. Possible role of microgliopathy in the pathogenesis of Nasu-Hakola disease. Clin Exp Neuroimmunol. 2013; 4 Suppl 1:17-26. source

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

    Interpretationcitation

    The possibility exists that an intense expression of ABI3 on microglia in NC, AD, and NHD brains might negatively regulate cell proliferation.

    “Therefore, the possibility exists that an intense expression of ABI3 on microglia in NC, AD, and NHD brains might negatively regulate cell proliferation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All the assays were performed in triplicate.

    “All the assays were performed in triplicate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The comprehensive examination by established neuropathologists validated the pathological diagnosis.

    “The comprehensive examination by established neuropathologists (YS and TI) validated the pathological diagnosis.”
    Quote in the paperSubstantial claim
36 of 36

  • The paper relies on this without support.

    The pattern of ABI3 expression in AD and NHD brains with relevance to microglial pathology remains to be characterized.

    “although the pattern of ABI3 expression in AD and NHD brains with relevance to microglial pathology remains to be characterized.”
    “However, the pattern of expression of ABI3 in the brains of AD, along with NHD with relevance to microglial pathology remains unknown.”

  • The paper relies on this without support.

    The precise biological function of ABI3 in microglia remains unknown.

    “At present, the precise biological function of ABI3 in microglia remains unknown.”

  • The paper relies on this without support.

    The mechanisms how functionally aberrant microglia evoke leukoencephalopathy remain unknown.

    “although the mechanisms how functionally aberrant microglia evoke leukoencephalopathy remain unknown.”

  • The paper relies on this without support.

    The precise molecular mechanism underlying AD remains largely unknown.

    “although the precise molecular mechanism underlying AD remains largely unknown.”
4 of 4

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Authors
Satoh, J.-I., Kino, Y., Yanaizu, M., Tosaki, Y., Sakai, K., Ishida, T., & Saito, Y.
Affiliations
  • Meiji Pharmaceutical University (JP)
  • National Center for Global Health and Medicine (JP)
  • National Center of Neurology and Psychiatry (JP)
ORCID
Venue
Intractable & Rare Diseases Research
Publisher
International Research and Cooperation Association for Bio & Socio-Sciences Advancement (IRCA-BSSA)
Published
2017
Volume
6
Issue
4
Pages
262-268
ISSN
  • 2186-361X (ISSN-L)
  • 2186-3644
DOI
10.5582/irdr.2017.01073
PMC
PMC5735279
OpenAlex
W2770258404
Semantic Scholar
9827751f03315ab4d04ee438ff4173893fd9d0f2
Cited by
55
References
56
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 5 · 2021: 11 · 2020: 8 · 2019: 4 · 2018: 2
FWCI
1.91
Type
journal article
Language
en
Open access
Locations
  • Intractable & Rare Diseases Research (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology (S1511016, 16K07043)
  • Ministry of Health, Labour and Welfare
  • Japan Society for the Promotion of Science (C25430054, 16K09683, 16K07043)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
ABI3, microglia, Alzheimer's disease, Nasu-Hakola disease, TREM2, TYROBP, actin cytoskeleton, amyloid plaques, microglial morphology, leukoencephalopathy, microglial migration, cell type-specific gene expression

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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 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

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