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Cited by 4Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease

Open access
Sun, Xiangyi, Pan, Sili, Li, Dandan, Su, Min, Zheng, Honghua, Zhang, Yun-wu, Li, Yanfang·2025·The Journal of Neuroscience
DOI 10.1523/jneurosci.0967-24.2025PMC PMC11884392
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Abstract

Accumulation of astrocytes around β-amyloid (Aβ) plaques is one of the earliest neuropathological changes in Alzheimer's disease (AD), but the underlying mechanisms and significance remain unclear. Cell adhesion molecule protocadherin-γC5 (Pcdh-γC5) has been reported to implicate in AD. Here, we find elevated expression levels of Pcdh-γC5 in the brain of 5×FAD mice and Aβ-treated astrocytes and further reveal that Pcdh-γC5 deficiency leads to exacerbated Aβ deposition in 5×FAD mice. Deletion of Pcdh-γC5 impairs astrocyte migration, astrocytic response to Aβ signaling, and Aβ phagocytosis in both cultured astrocytes in vitro and 5×FAD mice in vivo. Both male and female mice were used in this study. Our findings support a model in which increased expression level of Pcdh-γC5 promotes astrocyte migration in response to Aβ signaling and engulfment and phagocytosis of neurotoxic Aβ plaques, therefore exerting a critical neuroprotective function in AD.

AI snapshot

Written from the paper’s full text.

TL;DR

Pcdh-γC5 is elevated in 5×FAD mouse brain and Aβ-treated astrocytes, where it supports astrocyte migration, Aβ-induced recruitment, and phagocytosis of Aβ. Reducing Pcdh-γC5 exacerbates Aβ plaque pathology and cognitive impairment in 5×FAD mice, likely via impaired actin remodeling and PI3K-Akt signaling.

Key findings

  • Pcdh-γC5 expression increased in the cortex and hippocampus of 5×FAD mice and in cultured astrocytes after 1 μM oligomeric Aβ treatment for 16 and 24 h; EGTA blocked the Aβ-induced increase, indicating Ca²⁺ dependence.
  • In 5×FAD;Pcdhgc5+/− mice, the number and area of Aβ plaques were significantly elevated in cortex and hippocampus (n=5 mice), without significant changes in IL-1β, IL-6, TNF-α, microgliosis, APP/PS1 levels, soluble Aβ40/Aβ42, or neuronal loss.
  • Pcdh-γC5 deletion impaired astrocyte migration in wound-healing and transwell assays, abolished Aβ-induced astrocyte recruitment in vitro and around stereotaxically injected FAM-Aβ in vivo, and reduced phagocytosis of FAM-Aβ by mature astrocytes.
  • Astrocyte-specific Pcdh-γC5 shRNA in 5×FAD mice increased Aβ plaques and worsened Morris water maze performance, with increased escape latency on Days 5 and 6, longer swimming distance on Day 6, and fewer platform-region crossings (n=18 mice).

Methods

  • Mice included 5×FAD, Pcdhgc5 knockout, and WT C57BL/6J; both male and female mice were used, with specific ages including 2-month-old males for FAM-Aβ injection, 6–8-month-old mice for immunoblotting/immunofluorescence, and 6-month-old male 5×FAD mice for AAV injection.
  • Primary astrocytes were cultured from P0 mouse pups or 2-month-old male mice; oligomeric Aβ(1–42) was used at 1 μM, and astrocyte-specific Pcdh-γC5 knockdown used AAV-GfaABC1D-mCherry-WPRE with Pcdh-γC5 shRNA.
  • Main assays included immunoblotting, immunofluorescence, ELISA for Aβ40/Aβ42, wound healing, transwell migration, CCK-8 proliferation, FAM-Aβ phagocytosis with FACS, stereotaxic FAM-Aβ and AAV injection, and Morris water maze; statistics used t tests or one-way/two-way ANOVA with Tukey’s post hoc tests, significance at p<0.05.

Limitations

  • The paper states that GFAP mainly stains major astrocyte branches and may not label distal, synapse-proximal terminals well; it suggests using other astrocyte terminal markers or in vitro cultured astrocytes with prepared cerebral synaptosomes to better assess astrocytic synapse phagocytosis.
  • The paper notes that neonatal astrocytes did not show Aβ phagocytosis (data not shown), while mature astrocytes did, but the presented phagocytosis experiments focus on mature astrocytes.
  • Evident from the text: the in vivo plaque experiments used global Pcdhgc5+/− mice crossed with 5×FAD mice, while astrocyte specificity was addressed separately using AAV shRNA knockdown; a conditional astrocyte-specific knockout was not used for the plaque pathology experiments.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.0967-24.2025

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

15 of 40 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Gene expression alteration of Pcdh-γC5 has been detected in the brain of Alzheimer's disease patients and animal models of Alzheimer's disease, as well as neural cells generated from human iPSCs that express APOE4.

    “The gene expression alteration of Pcdh-γC5 has also been detected in the brain of AD patients and animal models of AD, as well as neural cells generated from human iPSCs that express APOE4, a prevalent genetic AD risk factor (Nativio et al., 2018;Meyer et al., 2019).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Nativio et al., 2018 source

      The Results section (‘H4K16ac is redistributed during normal aging and AD’; page unavailable) reports gene-expression analysis in human AD brain samples, but does not identify altered Pcdh-γC5 expression. Searches for Pcdh-γC5/PCDHGC5, animal models, and APOE4-expressing iPSC-derived neural cells found no passage in our copy establishing the specific claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Meyer et al., 2019 source

      The Results section on APOE4 and neuronal differentiation reports altered expression of other genes in APOE4 iPSC-derived neural progenitors and cerebral organoids. Our copy does not identify Pcdh-γC5 among them; searches for Pcdh-γC5, PCDHGC5, and protocadherin found no passage establishing the gene-specific claim. It also does not establish that alteration in AD patient or animal-model brains. (LLM, conf=0.80)

      Experimental — accuracy not yet measured
  • Premisecitation

    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)”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Wyss-Coray et al., 2003 source
    • cites Koistinaho et al., 2004 source
    • cites Kraft et al., 2013 source

      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
  • Premisecitation

    Pcdh-γC5 has been implicated in Alzheimer's disease pathogenesis.

    “Pcdh-γC5 has been implicated in AD pathogenesis (Nativio et al., 2018;Tao et al., 2024), prompting us to examine its expression in 5×FAD mice”
    • Also stated in: § Introduction · plain
      “further implicating Pcdh-γC5 in AD pathogenesis.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Nativio et al., 2018 source

      The Results section on AD-related H4K16ac changes discusses affected pathways but does not implicate Pcdh-γC5. Searches of our copy for “Pcdh-γC5,” “PCDHGC5,” and “protocadherin” found no passage addressing that gene’s role in AD pathogenesis. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites Tao et al., 2024 source

      The Results section on validation in MCI due to AD includes PCDHGC5 among differentially expressed proteins and identifies it as related to immune function. That supports an association with AD, but the paper does not establish a role for PCDHGC5 in AD pathogenesis. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Oláh et al., 2011

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

  • Premisecitation

    Pcdh-γC5 correlates with the level of both Aβ42 and phosphorylated tau (p-tau181) in cerebrospinal fluid of Alzheimer's disease patients.

    “Pcdh-γC5, a member of Pcdh-γs, was revealed to correlate with the level of both Aβ 42 and phosphorylated tau (p-tau 181 ), the two most prominent hallmarks of AD.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Tao et al., 2024 source
  • Premisecitation

    Pcdh-γC5 expression level increased significantly in the cerebrospinal fluid of Alzheimer's disease patients.

    “The expression level of Pcdh-γC5 increased significantly in the CSF of AD patients, highlighting Pcdh-γC5 as a potential early-stage biomarker of AD (Tao et al., 2024).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Tao et al., 2024 source

      The Results section on independent validation identifies PCDHGC5 as part of a 19-protein CSF panel for early diagnosis of MCI due to AD, supporting its potential as an early-stage biomarker. Our copy does not state that PCDHGC5 itself increased significantly: the passage explicitly reports upregulation for four other proteins, not PCDHGC5. Page numbers are unavailable in the indexed passages. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 10
  • May combine two claims. 30

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

    Premisecitation

    Aβ accumulation in the brain is one of the hallmarks of Alzheimer's disease and plays a key role in initiating and propagating Alzheimer's disease pathogenesis.

    “Accumulation of β-amyloid (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD) and plays a key role in initiating and propagating AD pathogenesis (Querfurth and LaFerla, 2010;Gomez-Arboledas et al., 2018).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Querfurth and LaFerla, 2010 source
    • cites Gomez-Arboledas et al., 2018 source

      The Introduction (page unavailable) identifies amyloid plaques as one of the two signature pathological lesions of Alzheimer’s disease, supporting the hallmark portion of the claim. The Discussion (page unavailable) discusses possible exacerbation of amyloid pathology, but does not establish that Aβ accumulation initiates and propagates Alzheimer’s disease pathogenesis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Reactive astrocytes accumulating around Aβ plaques constitute a neuroprotective barrier to prevent Aβ neurotoxicity spreading and phagocytose Aβ plaques.

    “It has been suggested that reactive astrocytes accumulating around Aβ plaques constitute a neuroprotective barrier to prevent not only Aβ neurotoxicity spreading but also phagocytose Aβ plaques (Konishi et al., 2022).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Konishi et al., 2022 source

      The Conclusions and Future Perspectives section says astrocytes phagocytose Aβ and that enhancing astrocytic lysosomal biogenesis promotes Aβ clearance and ameliorates plaque pathology. It does not say that reactive astrocytes accumulate around plaques or form a neuroprotective barrier that prevents Aβ neurotoxicity from spreading; searches for those points found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Pcdhs have been reported to regulate actin filament activity.

    “Since Pcdhs have been reported to regulate actin filament activity (Chen et al., 2009;Garrett et al., 2012;Keeler et al., 2015)”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Chen et al., 2009

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

    • cites Garrett et al., 2012 source
    • cites Keeler et al., 2015 source

      The Abstract and Discussion report that γ-protocadherins regulate FAK/PKC/MARCKS signaling and dendrite arborization. Our copy does not say that they regulate actin filament activity; searches for actin filaments, actin cytoskeleton, and actin filament activity found no passage establishing that point. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Accumulated reactive astrocytes surrounding Aβ plaques form a barrier to limit spreading of pathological Aβ and clear Aβ deposits through phagocytosis, exerting neuroprotective function in Alzheimer's disease.

    “accumulated reactive astrocytes have been commonly observed surrounding Aβ plaques, forming a barrier to limit the spreading of pathological Aβ in the brain parenchyma and clear Aβ deposits through phagocytosis, exerting neuroprotective function in AD (Verkhratsky et al., 2016;Preman et al., 2021;Konishi et al., 2022).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Verkhratsky et al., 2016

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

    • cites Preman et al., 2021 source

      Section 3.1 (page unavailable) reports reactive astrocytes near Aβ plaques, describes a potentially defensive response, and says astrocytes can help clear Aβ and exert neuroprotection. It does not say they form a barrier that limits Aβ spread; its specific example of plaque-associated astrocyte phagocytosis concerns neuritic dystrophies, not Aβ deposits. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Konishi et al., 2022 source

      The Conclusions and Future Perspectives section says astrocytes phagocytose Aβ and reports that enhancing astrocytic lysosomal biogenesis promotes Aβ clearance and ameliorates plaque pathology in AD mouse models. It does not say that reactive astrocytes surrounding plaques form a barrier that limits Aβ spread, so that part of the attributed claim is unsupported. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Reactive astrocytes exhibit hypertrophic characteristics with thick and long processes and increased expression level of glial fibrillary acidic protein (GFAP).

    “The reactive astrocytes exhibit hypertrophic characteristics with thick and long processes and increased expression level of glial fibrillary acidic protein (GFAP; Liddelow and Barres, 2017;Escartin et al., 2021).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Liddelow and Barres, 2017 source
    • cites Escartin et al., 2021 source

      The “GFAP as a marker” section says GFAP upregulation is prominent in many reactive astrocytes, but not all. “Morphology revisited” describes elongation and process extension in pathological contexts, yet cautions that GFAP staining can exaggerate hypertrophy and that cytoskeletal changes do not necessarily mean true hypertrophy. The source therefore does not support presenting thick, long processes and increased GFAP as characteristics of reactive astrocytes generally. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    PI3K-Akt signaling can regulate actin activity and is important in astrocyte proliferation and migration.

    “It has been suggested that PI3K-Akt signaling can regulate actin activity and is important in astrocyte proliferation and migration (Zhao et al., 2017;Liao et al., 2022;Pérez-Núñez et al., 2023).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Zhao et al., 2017 source
    • cites Liao et al., 2022 source
    • cites Pérez-Núñez et al., 2023 source

      The Discussion (page unavailable) says PI3K/AKT signaling regulates reactive astrocyte proliferation and participates in migration. The Background and Discussion identify regulation of the actin cytoskeleton as another altered pathway, but do not establish that PI3K/AKT signaling regulates actin activity. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Compared to WT astrocytes, deletion of Pcdh-γC5 did not alter the astrocyte area but significantly decreased the perimeter and the ratio of perimeter to area.

    “Compared to WT astrocytes, deletion of Pcdh-γC5 didn't alter the astrocyte area but significantly decreased the perimeter and the ratio of perimeter to area (Fig. 5A-D)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to WT mice, a significant decrease of neurons was observed in 5×FAD and 5×FAD;Pcdhgc5+/- mice, but with no significant difference between them.

    “Compared to WT mice, a significant decrease of neurons was observed in 5×FAD and 5×FAD;Pcdhgc5 +/- mice, but with no significant difference between them (Fig. 2K,L).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both the proportion of FAM-Aβ+ astrocytes and the FAM-Aβ intensity were significantly reduced in Pcdhgc5-/- mature astrocytes.

    “Both the proportion of FAM-Aβ+ astrocytes and the FAM-Aβ intensity were significantly reduced in Pcdhgc5 -/-mature astrocytes (Fig. 4C,D)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    mRNA levels of IL-1β, IL-6, and TNF-α were significantly enhanced in 5×FAD mice but unchanged with Pcdh-γC5 deficiency.

    “The mRNA levels of IL-1β, IL-6, and TNF-α were significantly enhanced in 5×FAD mice but unchanged with Pcdh-γC5 deficiency (Fig. 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Immunofluorescence staining showed increased Pcdh-γC5 clusters in the brain of 5×FAD mice, with some clusters colocalizing with neuronal marker MAP2 or astrocyte marker GFAP, especially around Aβ plaques.

    “Immunofluorescence staining showed increased Pcdh-γC5 clusters in the brain of 5×FAD mice, with some clusters colocalizing with neuronal marker MAP2 or astrocyte marker GFAP, especially around Aβ plaques (Fig. 1I-L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pcdh-γC5 is mainly expressed in neurons and astrocytes, with the highest expression level in astrocytes.

    “Pcdh-γC5 was found mainly expressed in neurons and astrocytes, with the highest expression level in astrocytes (Fig. 1B,C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Increased expression level of Pcdh-γC5 in the brain of 5×FAD mice and Aβ-treated astrocytes.

    “Increased expression level of Pcdh-γC5 in the brain of 5×FAD mice and Aβ-treated astrocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ treatment significantly increased the protein level ratios of both p-PI3K/PI3K and p-Akt/Akt in WT astrocytes, but not Pcdhgc5-/- astrocytes.

    “We found that Aβ treatment significantly increased the protein level ratios of both p-PI3K/PI3K and p-Akt/Akt in WT astrocytes, but not Pcdhgc5 -/-astrocytes (Fig. 5G-I)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to 5×FAD-Ctrl mice, 5×FAD-shRNA mice exhibited worse cognitive function, with significantly increased escape latency on Days 5 and 6 and longer swimming distance on Day 6 of training.

    “Compared to 5×FAD-Ctrl mice, 5×FAD-shRNA exhibited even worse cognitive function, with significantly increased escape latency on Days 5 and 6 and longer swimming distance on Day 6 of training (Fig. 8J,K).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Protein levels of APP and PS1 were significantly increased in 5×FAD mice, and Pcdh-γC5 deficiency did not alter the expression of APP and PS1.

    “The protein levels of both APP and PS1 were significantly increased in 5×FAD mice, and Pcdh-γC5 deficiency didn't alter the expression of APP and PS1 (Fig. 2G,H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For WT astrocytes, Aβ significantly accelerated actin reassembling, with cells that covered a significantly bigger area.

    “For WT astrocytes, Aβ significantly accelerated actin reassembling, with cells that covered a significantly bigger area.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the probe test, 5×FAD-shRNA mice crossed the platform region fewer times than WT and 5×FAD-Ctrl mice, aggravating cognitive impairment of 5×FAD mice.

    “The 5×FAD-shRNA mice crossed the platform region fewer times than WT and 5×FAD-Ctrl mice, aggravating the cognitive impairment of 5×FAD mice (Fig. 8L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neonatal astrocytes did not show any capability of Aβ phagocytosis, while mature astrocytes engulf FAM-Aβ well, exhibiting strong phagocytosis ability.

    “Neonatal astrocytes didn't show any capability of Aβ phagocytosis (data not shown), while mature astrocytes engulf FAM-Aβ pretty well, exhibiting strong phagocytosis ability.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Both cell migration and phagocytosis are processes dependent on actin remodeling and extension.

    “Both cell migration and phagocytosis are processes dependent on actin remodeling and extension (Cowin, 2005;Giralt et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cowin, 2005
    • cites Giralt et al., 2016

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

  • May combine two claims.

    Interpretationown data

    Pcdh-γC5 promotes astrocyte migration in response to Aβ signaling and phagocytosis of Aβ plaques, playing critical neuroprotective roles in AD pathogenesis.

    “Our research reveals that AD-susceptible protein Pcdh-γC5 promotes astrocyte migration in response to Aβ signaling and phagocytosis of Aβ plaques, playing critical neuroprotective roles in AD pathogenesis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 5×FAD mice are a valid model of Alzheimer's disease Aβ plaque pathogenesis and cognitive impairment relevant to human AD.

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

    Premisecitation

    A similar age-dependent expression result for Pcdh-γC5 was reported in the mouse brain.

    “A similar result was also reported in the mouse brain (Frank et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Frank et al., 2005 source

  • May combine two claims.

    Interpretationown data

    Pcdh-γC5 is essential in astrocyte accumulation and phagocytosis of Aβ plaques.

    “Collectively, these results indicate that Pcdh-γC5 is essential in astrocyte accumulation and phagocytosis of Aβ plaques.”
    • Also stated in: § Pcdh-γC5 is essential in astrocyte accumulation and phagocytosis of Aβ plaques · plain
      “Pcdh-γC5 is essential in astrocyte accumulation and phagocytosis of Aβ plaques.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pcdh-γC5 is critical in mediating astrocyte migration and Aβ-induced recruitment both in vitro and in vivo.

    “Taken together, these data reveal that Pcdh-γC5 is critical in mediating astrocyte migration and Aβ-induced recruitment both in vitro and in vivo.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    In this study, all experiments were blinded and randomized.

    “In this study, all experiments were blinded and randomized.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The experimental design, handling of mice, and data collecting and analyzing were identical across experiments.

    “The experimental design, handling of mice, and data collecting and analyzing were identical across experiments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    In the injected brain region, the mCherry signal of shRNA-AAV colocalized with astrocyte marker GFAP but not with neuronal marker NeuN, indicating specific infection of astrocytes.

    “In the injected brain region, the mCherry signal of shRNA-AAV colocalized with astrocyte marker GFAP well, but not with neuronal marker NeuN, indicating its specific infection of astrocytes (Fig. 8D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pcdh-γC5 is essential in astrocyte migration and phagocytosis of Aβ by regulating actin cytoskeletal dynamics, possibly through a downstream PI3K-Akt signaling pathway.

    “Together, we revealed that Pcdh-γC5 is essential in astrocyte migration and phagocytosis of Aβ by regulating actin cytoskeletal dynamics, possibly through a downstream PI3K-Akt signaling pathway.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pcdh-γC5 deficiency impairs Aβ-induced astrocyte accumulation and engulfment of Aβ plaques, leading to exacerbated plaque pathogenesis and cognitive impairment in 5×FAD mice.

    “Pcdh-γC5 deficiency impairs Aβ-induced astrocyte accumulation and engulfment of Aβ plaques, leading to exacerbated plaque pathogenesis and cognitive impairment in 5×FAD mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 5×FAD mice are a valid model of Alzheimer's disease Aβ plaque pathogenesis and cognitive impairment relevant to human AD.
    • Rests on an assumption: Pcdhgc5+/- heterozygosity reduces Pcdh-γC5 function sufficiently to model Pcdh-γC5 deficiency.

  • May combine two claims.

    Interpretationown data

    Deletion of Pcdh-γC5 implies reduced cellular protrusions and impaired actin cytoskeleton extension.

    “implying reduced cellular protrusions and impaired actin cytoskeleton extension.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Only mature astrocytes from adult mice, but not neonatal astrocytes, are capable of phagocytosing Aβ plaques.

    “It has been demonstrated that only mature astrocytes from adult mice, but not neonatal astrocytes, are capable of phagocytosing Aβ plaques (Wyss-Coray et al., 2003;Koistinaho et al., 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wyss-Coray et al., 2003 source
    • cites Koistinaho et al., 2004 source

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

    Premisecitation

    Phagocytosis ability of astrocytes is dependent on mouse age; only mature astrocytes cultured from adult, but not neonatal, mice are able to phagocytose and degrade Aβ, reducing Aβ plaques.

    “It has been reported that the phagocytosis ability of astrocytes is dependent on mouse age.Only mature astrocytes cultured from adult, but not neonatal, mice was able to phagocytose and degrade Aβ, reducing Aβ plaques (Wyss-Coray et al., 2003;Koistinaho et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wyss-Coray et al., 2003 source
    • cites Koistinaho et al., 2004 source
32 of 32

  • The paper relies on this without support.

    Reactive astrocytes also play a neuroprotective role by constituting a barrier around Aβ plaques and suppressing plaque progression in Alzheimer's disease.

    “However, it's increasingly appreciated that reactive astrocytes also play a neuroprotective role by constituting a barrier around Aβ plaques and suppressing plaque progression in AD.”

  • The paper relies on this without support.

    5×FAD mice are a valid model of Alzheimer's disease Aβ plaque pathogenesis and cognitive impairment relevant to human AD.

    “In this study, we have identified Pcdh-γC5 as a pivotal intracellular regulator of neuroprotective astrocytic response in a mouse model of AD.”

  • The paper relies on this without support.

    Pcdhgc5+/- heterozygosity reduces Pcdh-γC5 function sufficiently to model Pcdh-γC5 deficiency.

    “we compared the amount of astrocytes surrounding Aβ plaques in the brain of 5×FAD and 5×FAD;Pcdhgc5 +/-mice”

  • The authors state this as an assumption.

    Aβ colocalized with astrocytes in three-dimensional reconstruction is phagocytosed Aβ.

    “Aβ colocalized with astrocytes were considered phagocytosed Aβ.”

  • The paper relies on this without support.

    The astrocyte-specific AAV shRNA knockdown of Pcdh-γC5 does not have off-target effects on other genes.

    “astrocyte-specific AAV containing Pcdh-γC5 shRNA”
5 of 5

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.

  • Transwell incubation time differs between methods and figure legend

    Minor

    The methods say the transwell assay was incubated for 36 h, whereas the Figure 3 legend says the astrocytes were incubated for 24 h.

  • S-100β result cites the wrong figure

    Minor

    The text attributes the S-100β result to Figure 2H,I, but the figure legend places that experiment in Figure 3H,I.

2 of 2

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Authors
Sun, X., Pan, S., Li, D., Su, M., Zheng, H., Zhang, Y.-W., & Li, Y.
Affiliations
Xiamen University (CN)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2025-01-22
Volume
45
Issue
10
Pages
e0967242025
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.0967-24.2025
PMC
PMC11884392
OpenAlex
W4406729382
Cited by
4
References
62
Citations by year
2026: 1 · 2025: 3
FWCI
2.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
MOST | National Natural Science Foundation of China (82071195, 81870845, 82271219)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloid plaques, astrocytes, astrocyte migration, 5xFAD mice, neuroprotection, adhesion molecules, sex differences
MeSH terms
Protocadherins, Alzheimer Disease, Animals, Astrocytes, Cell Movement, Cells, Cultured, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Phagocytosis, Cadherins, Amyloid beta-Peptides, Mice, Knockout, Mice, Plaque, Amyloid

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 2026-11-02.

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

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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

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

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