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Cited by 16Alzheimer's disease research and treatmentsProteoglycans and glycosaminoglycans researchNeuroinflammation and Neurodegeneration Mechanisms

Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration

Open access
Logsdon, Aric F., Foresi, Brian, Hu, Shannon J., Quah, Emily, Meuret, Cristiana J., Le, Jaden P., Hendrickson, Aarun S., Redford, Ingrid K. +8 more·2024·Journal of Neurochemistry
DOI 10.1111/jnc.16067PMC PMC11298576
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical symptoms of memory and cognitive deficiencies. Postmortem evaluation of AD brain tissue shows proteinopathy that closely associate with the progression of this dementing disorder, including the accumulation of extracellular beta amyloid (Aβ) and intracellular hyperphosphorylated tau (pTau) with neurofibrillary tangles (NFTs). Current therapies targeting Aβ have limited clinical efficacy and life‐threatening side effects and highlight the need for alternative treatments targeting pTau and other pathophysiologic mechanisms driving AD pathogenesis. The brain's extracellular matrices (ECM), particularly perineuronal nets (PNNs), play a crucial role in brain functioning and neurocircuit stability, and reorganization of these unique PNN matrices has been associated with the progression of AD and accumulation of pTau in humans. We hypothesize that AD‐associated changes in PNNs may in part be driven by the accumulation of pTau within the brain. In this work, we investigated whether the presence of pTau influenced PNN structural integrity and PNN chondroitin sulfate‐glycosaminoglycan (CS‐GAG) compositional changes in two transgenic mouse models expressing tauopathy‐related AD pathology, PS19 (P301S) and Tau4RTg2652 mice. We show that PS19 mice exhibit an age‐dependent loss of hippocampal PNN CS‐GAGs, but not the underlying aggrecan core protein structures, in association with pTau accumulation, gliosis, and neurodegeneration. The loss of PNN CS‐GAGs were linked to shifts in CS‐GAG sulfation patterns to favor the neuroregenerative isomer, 2S6S‐CS. Conversely, Tau4RTg2652 mice exhibit stable PNN structures and normal CS‐GAG isomer composition despite robust pTau accumulation, suggesting a critical interaction between neuronal PNN glycan integrity and neighboring glial cell activation. Overall, our findings provide insights into the complex relationship between PNN CS‐GAGs, pTau pathology, gliosis, and neurodegeneration in mouse models of tauopathy, and offer new therapeutic insights and targets for AD treatment. image

AI snapshot

Written from the paper’s full text.

TL;DR

In two tauopathy mouse models, hippocampal perineuronal net (PNN) chondroitin sulfate glycosaminoglycan (CS-GAG) loss occurred in PS19 mice with age, pTau, gliosis, and neurodegeneration, while PNN core protein remained stable; Tau4RTg2652 mice with robust pTau but no gliosis showed stable or increased PNNs. PS19 PNN glycan loss was accompanied by a shift toward 2S6S-CS and correlated with pTau, gliosis, and neuronal TUNEL in the dentate gyrus.

Key findings

  • In 9-month-old PS19 mice, hippocampal WFA+ PNN CS-GAGs decreased by 58.5% (p<0.0001) alongside increased pTau, GFAP astrogliosis, and Iba1 microgliosis (all p<0.0001), with no significant change in aggrecan core protein (p=0.63) or Cat-315 aggrecan labeling (p=0.75).
  • In 6-month-old PS19 mice, CA3 pTau was increased (p=0.003) without astrogliosis (p=0.72) or microgliosis (p=0.77), and WFA+ PNN CS-GAGs showed only a slight 13.7% decrease (p=0.04); 3-month-old PS19 mice showed no PNN changes.
  • In 4-month-old Tau4RTg2652 mice, robust hippocampal pTau accumulation (p<0.0001) occurred without astrogliosis (p=0.50), and both WFA+ PNN CS-GAGs (p=0.004) and aggrecan+ PNN core protein (p<0.0001) were increased.
  • In 9-month-old PS19 mice, hippocampal CS sulfation shifted with decreased 6S-CS (p=0.02) and increased 2S6S-CS (p=0.02); 2S6S-CS correlated most strongly with WFA+ PNN loss (R²=0.45), microgliosis (R²=0.42), and astrogliosis (R²=0.36). Dentate gyrus TUNEL increased (p=0.02), 77.8% of TUNEL colocalized with neurons, and TUNEL correlated with pTau (p=0.004), GFAP (p<0.0001), Iba1 (p<0.0001), decreased 6S-CS (p=0.03), and increased 2S6S-CS (p=0.01), but not WFA+ PNN loss.

Methods

  • Cross-sectional comparison of transgenic tauopathy mice versus age-matched wild-type littermates: PS19 at 3 months (n=9 WT, n=8 PS19), 6 months (n=8 WT, n=10 PS19), and 9 months (n=10 WT, n=10 PS19), plus Tau4RTg2652 at 4 months (n=8 WT, n=7 Tg2652).
  • Immunofluorescence with stereological mean fluorescence intensity quantification for WFA (PNN CS-GAGs), aggrecan, Cat-315, GFAP, Iba1, and AT8 pTau across hippocampal subregions; TUNEL staining with NeuN, GFAP, Iba1, and Olig2 colocalization.
  • Chondroitinase ABC digestion of fixed hippocampal sections followed by LC-MS/MS with multiple reaction monitoring to quantify relative CS disaccharide isomers; statistical analyses used GraphPad Prism 10 with t-tests/Mann-Whitney, 2-way ANOVA/mixed effects, and linear regression, with blinded quantitative analyses.

Limitations

  • Stated: bulk hippocampal CS-GAG analysis may not reflect intraregional or cell-specific changes; bulk LC-MS/MS may also detect CS sulfation from non-PNN matrices such as interstitial matrix and glial-scarring deposits; WFA binding is not a universal PNN CS-GAG label and preferentially recognizes 0S-CS, though the authors did not observe significant 0S-CS differences in 9-month PS19 mice.
  • Evident: the study is largely correlational, so it cannot establish that pTau, gliosis, or neurodegeneration causally drive PNN CS-GAG loss or CS isomer shifts.
  • Evident: no behavioral or cognitive outcomes are reported, and despite mixed-sex cohorts, no sex-stratified analyses are presented.

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

Integrity signals

Registry

Crossref · 10.1111/jnc.16067

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

33 of 58 cited sources checked · 11 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    About 40% of patients treated with aducanumab experienced life-threatening side effects, including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H).

    “about 40% of patients treated with the mab aducanumab experienced life-threatening side effects, including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Budd Haeberlein et al. 2022 source

      The Safety section identifies ARIA-E and ARIA-H as adverse events, but it does not characterize roughly 40% of treated patients as having life-threatening effects. It reports serious ARIA events in only 1.5% and 1.4% of the high-dose groups, says a minority of participants with ARIA had symptoms, and reports no fatal ARIA events. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Recent therapies targeting Aβ clearance using anti-Aβ monoclonal antibodies during early stages of AD provide minimal cognitive benefit.

    “Recent therapies targeting Aβ clearance using anti-Aβ monoclonal antibodies (mabs) during the early stages of AD provide minimal cognitive benefit”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Shi et al. 2022 source
    • cites van Dyck et al. 2023 source

      The Abstract and Discussion report that lecanemab reduced brain amyloid and produced moderately less decline in cognition and function than placebo at 18 months in people with early Alzheimer’s disease. The paper does not characterize that benefit as “minimal,” and its trial of one antibody does not establish the claim about therapies in general. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Sims et al. 2023 source

      The Primary Outcome section reports that donanemab slowed decline on a cognition-and-function scale by 35.1% in the low/medium-tau group and 22.3% in the combined group versus placebo. The Discussion explicitly calls the benefit clinically meaningful, contrary to describing the benefit as minimal. This trial evaluates donanemab, not every anti-Aβ antibody. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    The Tg2576/APPsw and APPNL-F mouse lines of amyloidosis showed no change in hippocampal PNN abundance or distribution compared to controls.

    “while the Tg2576/APPsw and APPNL-F mouse lines of amyloidosis showed no change in hippocampal PNN abundance or distribution compared to controls (Morawski et al. 2010b; Sos et al. 2020).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Morawski et al. 2010b

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

    • cites Sos et al. 2020 source

      The Results section, “PV IN-specific perineuronal nets do not change in APPNL-F mice” (page unavailable), reports no evidence of PNN deterioration in a qualitative comparison of APPNL-F mice and WT littermates. That supports unchanged PNN coverage around hippocampal PV neurons, but the paper does not establish unchanged PNN abundance or distribution throughout the hippocampus. The Tg2576/APPsw line is separately cited to Morawski et al., so it is not assessed against Sos et al. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    AD-associated PNN loss is characterized by selective deglycosylation of PNN CSPGs instead of core protein degradation and total loss of PNN matrices.

    “These reports imply that AD-associated ‘PNN loss’ is characterized by selective deglycosylation of the PNN CSPGs instead of core protein degradation and total loss of the PNN matrices themselves (Scarlett et al. 2022).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Scarlett et al. 2022 source

      The Figure 9 caption and Conclusions (page unavailable) propose that apparent PNN loss in AD may reflect remodeling rather than degradation of the entire matrix. They attribute reduced WFA labeling chiefly to altered CS-GAG sulfation and lectin recognition, not established selective deglycosylation. The claim therefore supports the matrix-remodeling distinction but overstates and misidentifies the proposed glycan mechanism. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Loss of PNN CS-GAGs appears to occur independently to PNN core proteins (aggrecan and brevican), which remain stable in postmortem AD brain tissue.

    “Intriguingly, the loss of PNN CS-GAGs appears to occur independently to PNN core proteins (i.e., aggrecan and brevican), which remain stable in postmortem AD brain tissue (Brückner et al. 1999; Morawski et al. 2010a; Morawski et al. 2012; Lendvai et al. 2013; Howell et al. 2015).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Brückner et al. 1999 source
    • cites Morawski et al. 2010a

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

    • cites Morawski et al. 2012 source

      The Discussion (Technical considerations; page not available) reports that prolonged post-mortem delay substantially reduced WFA binding to chondroitin-associated sites while aggrecan reactivity was virtually unaffected. But it attributes that loss to post-mortem changes, not AD: WFA and VVA binding was retained in well-preserved AD and control tissue. The paper also identifies brevican with perisynaptic axonal coats rather than PNNs and reports its loss in plaque cores. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 36
  • The quote only partly states this claim. 3

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

    Premisecitation

    One study by Yang et al. showed no difference in the number of PNNs within the perirhinal cortex of 3-month-old TauP301S (PS19) mice compared to age-matched controls.

    “Although one study by Yang et al. showed no difference in the number of PNNs within the perirhinal cortex of 3-month-old TauP301S (PS19) mouse model of tauopathy compared to age-matched controls (Yang et al. 2015)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Yang et al. 2015 source

      Materials and methods (Mice; Stereology; pages unavailable) describe age-matched controls for Tg P301S mice and counting PNN-positive cells in the perirhinal cortex. However, the Results (Progressive memory loss in Tg P301S mice; page unavailable) report neuronal loss at three months, not a finding of no difference in PNN numbers. Our copy therefore supports the study context but not the claimed PNN result or the PS19 designation. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    4-month-old 5xFAD mice that overexpress Aβ exhibit a significant decrease in WFA+ PNNs in the cortex and subiculum.

    “4-month-old 5xFAD mice that overexpress Aβ exhibit a significant decrease in WFA+ PNNs in the cortex and subiculum (Crapser et al. 2020)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Crapser et al. 2020 source

      The Results (page not provided) report significantly reduced WFA+ PNN area in the 5xFAD subiculum at 4 months compared with age-matched WT mice. They report significant loss in the visual cortex only from 8 months onward, so the claimed significant cortical decrease at 4 months is not supported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Mean fluorescence intensity of WFA, ACAN, GFAP, and Cat-315 was performed based on an established method for PNN quantification and applied using a stereological approach.

    “Mean fluorescence intensity (MFI) of WFA, ACAN, GFAP, and Cat-315 were performed based on an established method for PNN quantification (Slaker et al. 2016) and applied using a stereological approach.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Slaker et al. 2016 source

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

    Interpretationcitation

    The rTg4510 study implicates pTau and/or gliosis as a driver for PNN CS-GAG loss.

    “Although this study implicates pTau and/or gliosis as a driver for PNN CS-GAG loss, core protein abundance was not examined.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kudo et al. 2023 source

      The Results section reports reduced WFA labeling of PNNs in six-month-old rTg4510 mice, alongside microglial activation. The Discussion suggests that glial proteases might mediate PNN degradation as tau pathology progresses, but it does not establish pTau or gliosis as a causal driver or specifically measure CS-GAG loss. No page numbers are available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    ACAN+ PNNs remain intact in 9m-PS19 mice, confirmed after staining with a second antibody against aggrecan, Cat-315 (p=0.75).

    “The finding that PNN core proteins remain intact in 9m-PS19 mice was confirmed after staining with a second antibody against aggrecan, Cat-315 (p=0.75) (Supplemental Fig. 1) (Matthews et al. 2002)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Matthews et al. 2002 source

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

    Premisecitation

    CS-GAGs are comprised of repeating units of glucuronic acid and N-acetylgalactosamine isomers that are uniquely modified by the addition of sulfates to the disaccharide unit, including non-sulfated (0S-CS), mono-sulfated (4S-CS and 6S-CS), and di-sulfated (2S6S-CS and 4S6S-CS) variants.

    “These CS-GAGs are comprised of repeating units of glucuronic acid and N-acetylgalatosamine isomers that are uniquely modified by the addition of sulfates to the disaccharide unit, including non-sulfated (0S-CS), mono-sulfated (4S-CS and 6S-CS), and di-sulfated (2S6S-CS and 4S6S-CS) variants (Fig. 4A) (Djerbal et al. 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Djerbal et al. 2017 source

      The Introduction and Fig. 1 caption describe repeating glucuronic acid–N-acetylgalactosamine disaccharides and identify the sulfation positions corresponding to the listed mono- and di-sulfated variants. They do not identify a non-sulfated 0S-CS variant, so that part of the list is not directly supported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Tg2652 mice exhibit early accumulation of pTau but live a normal life span without gliosis or neuronal loss.

    “Tg2652 mice exhibit early accumulation of pTau but live a normal life span without gliosis or neuronal loss (Wheeler et al. 2015).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Wheeler et al. 2015 source

      The Results (Fig. 1) show phosphorylated tau by three months and report an approximately normal lifespan. The Discussion reports no evidence of focal or widespread neuronal loss. Our copy does not establish the claimed absence of gliosis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The relative abundance of CS isomers incorporated into CS-GAG chains has been linked to key biological functions within the brain, including charged molecule diffusion (0S-CS), neurocircuit plasticity (4S-CS and 6S-CS), glial scarring (4S6S-CS), and neurite outgrowth (2S6S-CS).

    “The relative abundance of CS isomers incorporated into the CS-GAG chains has been linked to key biological functions within the brain including charged molecule diffusion (0S-CS (Nicholson & Hrabětová 2017)), neurocircuit plasticity (4S-CS and 6S-CS (Miyata et al. 2012; Yang et al. 2021)), glial scarring (4S6S-CS (Brown et al. 2012)), and neurite outgrowth (2S6S-CS (Shida et al. 2019; Clement et a”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Nicholson & Hrabětová 2017 source

      The citation to Nicholson and Hrabětová is attached to charged-molecule diffusion (0S-CS), not the other functions in the sentence. In “Extracellular matrix and the control of ECS properties” (page unavailable), the paper reports that chondroitin sulfate affects Ca2+ diffusion, but it does not identify the 0S-CS isomer or link its relative abundance to that effect. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Miyata et al. 2012 source
    • cites Brown et al. 2012 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Microgliosis represents a potential mechanism driving PNN loss in models of neurodegeneration.

    “Recent work suggests that microgliosis represents a potential mechanism driving PNN loss in models of neurodegeneration (Miyata et al. 2012; Miyata & Kitagawa 2016; Crapser et al. 2021)”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Miyata et al. 2012 source
    • cites Miyata & Kitagawa 2016 source

      The Introduction and Results §3.3 describe altered PNNs in mice with increased chondroitin 6-sulfation, while the Discussion addresses aggrecan condensation and glia-dependent PNN formation. Searches for microgliosis, microglial PNN degradation, and neurodegeneration found no passage linking microgliosis to PNN loss in models of neurodegeneration. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites Crapser et al. 2021 source

  • May combine two claims.

    Premisecitation

    Unlike other pain-relievers, diclofenac represses the release of the inflammatory cytokine interleukin-1β and reduces activation of microglia.

    “Unlike the other pain-relievers, diclofenac represses the release of the inflammatory cytokine interleukin-1β and reduces activation of microglia (Stopschinski et al. 2023).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Stopschinski et al. 2023 source

      In “Mechanisms of action beyond COX inhibition” (page not provided), the review reports that diclofenac had a modest effect on IL-1β release. It attributes reduced microglial activation to mefenamic acid, not diclofenac, and the reported comparison with other NSAIDs concerns fenamates rather than diclofenac. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

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

    Premisecitation

    TUNEL staining detects DNA breaks formed during cellular apoptosis and is a widely applied histological method used to measure neurodegeneration.

    “TUNEL staining, which detects DNA breaks formed during cellular apoptosis, is a widely applied histological method used to measure neurodegeneration (Linsley et al. 2019).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Linsley et al. 2019 source

      The “High throughput cell death screening assays” section says TUNEL monitors DNA fragmentation preceding death and was used to read out neuronal death in a β-amyloid toxicity screen. It does not describe TUNEL as a widely applied histological measure of neurodegeneration or say that the DNA breaks it detects are specific to apoptosis; the “Apoptosis” section cautions that neurodegenerative cell death is not exclusively apoptotic. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The anti-inflammatory drug diclofenac was recently found to associate with the slowing of cognitive decline.

    “However, the anti-inflammatory drug diclofenac was recently found to associate with the slowing of cognitive decline (Stuve et al. 2020).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Stuve et al. 2020 source

  • May combine two claims.

    Premisecitation

    Central administration of FGF-1 into rats induces >2x increase in WFA+ PNNs after 24h and significantly increases the relative abundance of the 2S6S-CS isomer.

    “We recently showed that central administration of FGF-1 into rats 1) induces >2x increase in WFA+ PNNs after 24h, and 2) significantly increases the relative abundance of the 2S6S-CS isomer (Alonge et al. 2020).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Alonge et al. 2020 source

      The main text and Extended Data Fig. 2 report a significant increase in arcuate PNN fluorescence 24 hours after central FGF1 injection in Wistar rats, but the text provided does not establish the claimed >2-fold magnitude. The main text reports increased Δ2S6S-CS in FGF1-treated ZDF rats, measured 24 days after injection, not at the 24-hour assessment. The Methods describe CS isomers as relative percentages of total CS composition. (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

    Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs may reduce the risk of AD, but the majority of NSAIDs fail to reduce the prevalence of AD or influence the progression of AD-associated cognitive decline.

    “Although epidemiological evidence suggest that non-steroidal anti-inflammatory drugs may reduce the risk of AD, the majority of NSAIDs fail to reduce the prevalence of AD or influence the progression of AD-associated cognitive decline (Rivers-Auty et al. 2020).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Rivers-Auty et al. 2020 source

      The Introduction reports epidemiological evidence associating NSAID use with a lower risk of developing Alzheimer’s disease. It also says the study examined cognitive decline rather than incidence or prevalence; the Results found no significant change in cognitive decline for most NSAIDs studied. The claim that most NSAIDs fail to reduce Alzheimer’s disease prevalence is therefore not established by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The authors recently reported striking regional differences in brain CS-GAG composition throughout wt mouse brain tissue.

    “Indeed, we recently reported striking regional differences in brain CS-GAG composition throughout wt mouse brain tissue (Scarlett et al. 2022)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Scarlett et al. 2022 source

  • May combine two claims.

    Premisecitation

    WFA binding affinity is highly influenced by the abundance of 0S-CS isomer units incorporated into the PNN CS-GAGs, and WFA should not be thought of as a universal, non-specific histological label for PNN CS-GAGs.

    “WFA binding affinity is highly influenced by the abundance of 0S-CS isomer units incorporated into the PNN CS-GAGs, and as such, should not be thought of as universal, non-specific histological label for PNN CS-GAGs (Scarlett et al. 2022; Härtig et al. 2022).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Scarlett et al. 2022 source
    • cites Härtig et al. 2022 source

      The Introduction (page not specified) says WFA specifically interacts with non-sulfated tetrasaccharides, and the Results and Discussion report PNNs that are aggrecan-immunoreactive but WFA-negative. This supports the caution that WFA is not a universal, non-specific label. The paper does not state that WFA binding affinity is highly influenced by the abundance of 0S-CS isomer units in PNN CS-GAGs. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Tau4RTg2652 mice exhibit stable PNN structures and normal CS-GAG isomer composition despite robust pTau accumulation.

    “Conversely, Tau4RTg2652 mice exhibit stable PNN structures and normal CS-GAG isomer composition despite robust pTau accumulation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 9m-PS19 mouse brain tissue, the strongest correlation occurred between 2S6S-CS and the loss of WFA+ PNNs (R2=0.45), followed by 2S6S-CS and the induction of microgliosis (R2=0.42) and astrogliosis (R2=0.36).

    “we note that the strongest correlation occurred between 2S6S-CS and the loss of WFA+ PNNs (R2=0.45) followed by 2S6S-CS and the induction of microgliosis (R2=0.42) and astrogliosis (R2=0.36).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In 9m-PS19 mice, changes in 6S-CS and 2S6S-CS isomer abundance significantly correlated with elevation in microgliosis.

    “microgliosis (p=0.02, p=0.006) (Fig. 4G)”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In 9m-PS19 mice, changes in 6S-CS and 2S6S-CS isomer abundance significantly correlated with elevation in astrogliosis.

    “elevation in both astrogliosis (p=0.02, p=0.007) (Fig. 4F)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    6m-PS19 mice showed intraregional differences in hippocampal pTau accumulation, with the CA3 region exhibiting the greatest accumulation of pTau at this age (p=0.003).

    “stereology analysis of 6m-PS19 mice showed intraregional differences in hippocampal pTau accumulation (Fig. 2A), with the CA3 region exhibiting the greatest accumulation of pTau at this age (p=0.003).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In 9m-PS19 mice, compared to age-matched wt littermate controls, hippocampal CS sulfation patterning shifts, with decreased monosulfated 6S-CS isomer abundance (p=0.02) and increased disulfated 2S6S-CS isomer abundance (p=0.02).

    “Compared to age-matched, wt littermate controls, we observed a clear shift in 9m-PS19 hippocampal CS sulfation patterning, including decreased monosulfated 6S-CS isomer (p=0.02) and increased disulfated 2S6S-CS isomer (p=0.02) abundance (Fig. 4B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study shows an age-dependent loss in PNN CS-GAGs without changes in PNN core protein abundance in the PS19 mouse model of tauopathy.

    “Here, the results of our study show an age-dependent loss in PNN CS-GAGs without changes in PNN core protein abundance in the PS19 mouse model of tauopathy”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The inflection point for PNN CS-GAG changes in PS19 mice appears to emerge at 6 months of age, where both the appearance of increased pTau accumulation specific to the CA3 hippocampal subregion and loss of WFA+ PNNs are first observed.

    “The inflection point for PNN CS-GAG changes in PS19 mice appears to emerge at 6 months of age, where both the appearance of increased pTau accumulation specific to the CA3 hippocampal subregion and loss of WFA+ PNNs are first observed (Fig. 2).”
    Quote in the paperSubstantial claim

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

    Findingown data

    The increase in 2S6S-CS abundance observed in 9m-PS19 mice mirrors the increase in cortical 2S6S-CS isomer expression in demented Braak V/VI patients, and also increases after considerable pTau accumulation and gliosis at this age.

    “This finding mirrors the increase in 2S6S-CS abundance observed in 9m-PS19 mice (Fig. 4), which also increases after considerable pTau accumulation and gliosis at this age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The authors did not observe the same changes in PS19 mice; specifically, there were no discernable differences in 6S-CS isomer expression in the presence of low pTau (6m-PS19 mice) or robust pTau accumulation (4m-Tg2652 mice).

    “However, we did not observe the same changes in PS19 mice. Specifically, we report no discernable differences in 6S-CS isomer expression in the presence of low pTau (6m-PS19 mice), or robust pTau accumulation (4m-Tg2652 mice) (Supplemental Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Changes in PNN CS-GAG abundance occurred in parallel to changes in CS-GAG composition, which included increased expression of the 2S6S-CS neuroregenerative isomer.

    “Changes in PNN CS-GAG abundance occurred in parallel to changes in CS-GAG composition, which included increased expression of the 2S6S-CS neuroregenerative isomer (Fig. 4)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    3-month-old PS19 mice do not exhibit gliosis or changes in PNN matrices.

    “gliosis, or changes in PNN matrices (Supplemental Fig. 1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PS19 mice exhibit an age-associated loss of WFA+ PNNs, in the absence of changes in PNN core protein abundance, and this effect was exacerbated in the presence of gliosis and neurodegeneration.

    “We revealed that PS19 mice exhibit an age-associated loss of WFA+ PNNs, in the absent of changes in PNN core protein abundance, and that this effect was exacerbated in the presence of gliosis and neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The lack of PNN changes in mouse models of Aβ agrees with human studies that show no significant overlap between extracellular Aβ deposits and PNN distribution in AD brain tissue.

    “The lack of PNN changes in mouse models of Aβ agree with human studies that show no significant overlap between extracellular Aβ deposits and PNN distribution in AD brain tissue (Morawski et al. 2010a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Morawski et al. 2010a

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

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    PNNs play a crucial role in brain functioning and neurocircuit stability.

    “The brain’s extracellular matrices (ECM), particularly perineuronal nets (PNNs), play a crucial role in brain functioning and neurocircuit stability”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The APP/PS1 mouse model of Aβ overexpression exhibits a significant increase in hippocampal WFA+ labeling of PNN CS-GAGs surrounding parvalbumin neurons.

    “The APP/PS1 mouse model of Aβ overexpression exhibits a significant increase in hippocampal WFA+ labeling of PNN CS-GAGs surrounding parvalbumin neurons (Végh et al. 2014)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Végh et al. 2014

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

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

    Premisecitation

    Accumulation of Aβ and intracellular pTau are considered hallmark neuropathologic criteria for diagnosing AD progression.

    “The accumulation of Aβ and intracellular pTau are considered the hallmark neuropathologic criteria for diagnosing the AD progression (Braak & Braak 1991).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Braak & Braak 1991 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The authors previously optimized a liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique capable of quantifying the relative abundance of each non-, mono-, and di-sulfated CS isomer extracted from fixed mouse and human brain tissues using ChABC enzymatic digestion.

    “We previously optimized a liquid chromatography–tandem mass spectrometry (LC-MS/MS) technique capable of quantifying the relative abundance of each non-, mono-, and di-sulfated CS isomer extracted from fixed mouse and human brain tissues using ChABC enzymatic digestion (Alonge et al. 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Alonge et al. 2019 source

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

    Study design and conductnone given

    All experiments reported follow the ARRIVE guidelines.

    “All experiments reported follow the ARRIVE guidelines.”
    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 conductown data

    A power analysis for the main effect (loss of PNN CS glycans) was performed on the 9m-PS19 cohort; a mean difference of 58.5% was determined between wt controls and 9m-PS19 mice, resulting in 13 for the (Z1-alpha/2+Z1-beta) squared value and a minimum sample size of n=2 to confirm alpha level of 0.05 at 95% power.

    “a mean difference of 58.5% was determined between wt controls vs 9m-PS19 mice, resulting in 13 for the (Z1-alpha/2+Z1-beta) squared value and a minimum sample size of n=2 to confirm alpha level of 0.05 at 95% power.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Investigators were blinded to study conditions during all quantitative analyses.

    “Investigators were blinded to study conditions during all quantitative analyses.”
    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

    No pre-determined exclusion criteria were utilized in this study, all animals were included, outlier tests were not performed, and all viable data resulting from the analyses were included in this manuscript.

    “No pre-determined exclusion criteria were utilized in this study, all animals were included, outlier tests were not performed, and all viable data resulting from the analyses were included in this manuscript.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PS19 mice exhibit age-dependent accumulation of pTau, microgliosis, and neurodegeneration from 3 to 9 months of age, resulting in a shortened life span (9-12 months of age).

    “Whereas PS19 mice exhibit age-dependent accumulation of pTau, microgliosis, and neurodegeneration from 3 to 9 months of age, resulting in a shortened life span in this model (9–12 months of age) (Yoshiyama et al. 2007)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yoshiyama et al. 2007 source

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

    Study design and conductnone given

    All animals were housed and handled in accordance with protocols approved by the University of Washington and the Veterans Affairs Puget Sound Health Care System's IACUC.

    “All animals were housed and handled in accordance with protocols approved by the University of Washington and the Veterans Affairs Puget Sound Health Care System’s Institutional Animal Care and Use Committee (IACUC)”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Neurodegeneration is a hallmark of AD in both demented patients and aged PS19 mice.

    “Neurodegeneration is a hallmark of AD in both demented patients and aged PS19 mice (Yoshiyama et al. 2007; Terry et al. 1991).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yoshiyama et al. 2007 source
    • cites Terry et al. 1991 source

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

    Study design and conductcitation

    CS disaccharides were isolated and quantified according to previously published methods.

    “CS disaccharides were isolated and quantified according to our previously published methods (Alonge et al. 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Alonge et al. 2019 source

  • May combine two claims.

    Interpretationown data

    9m-PS19 mice exhibit regional PNN deglycosylation without changes in ACAN core protein abundance, like that observed in postmortem brains of human AD patients.

    “Overall, these results show 9m-PS19 mice exhibit regional PNN deglycosylation without changes in ACAN core protein abundance, like that observed in postmortem brains of human AD patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The two-step increase suggests that the elevation in brain 6S-CS isomer occurs prior to the development of AD clinicopathology in humans, which is then further elevated in the demented brain.

    “This two-step increase suggests that the elevation in brain 6S-CS isomer occurs prior to the development of AD clinicopathology in humans, which is then further elevated in the demented brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Whereas increased 6S-CS may drive the appearance of pTau in humans, it does not appear necessary for pTau expression in PS19 or Tg2652 mice.

    “We interpret these results to suggest that whereas increased 6S-CS may drive the appearance of pTau in humans, it does not appear necessary for pTau expression in PS19 or Tg2652 mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    By investigating two different mouse models of tauopathy, this body of work distinguishes age-associated changes in PNNs with pTau load and additional AD-associated pathologies, including gliosis and neurodegeneration.

    “By investigating two different mouse models of tauopathy, this body of work distinguishes age-associated changes in PNNs with pTau load and additional AD-associated pathologies, including gliosis and neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Neuronal loss itself does not drive the loss of WFA+ PNNs but may directly influence their CS-GAG compositions.

    “implying neuronal loss itself does not drive the loss of WFA+ PNNs but may directly influence their CS-GAG compositions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    There are similarities between pTau-associated CS-GAG compositional changes in human AD brain and 9m-PS19 mice, but there are also critical differences between these two datasets.

    “Although there are similarities between pTau-associated CS-GAG compositional changes in human AD brain and 9m-PS19 mice, we note some critical differences between these two datasets.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both pTau accumulation and increased gliosis observed in 9m-PS19 mice may play a role in neurodegeneration within the DG, potentially contributing to the cognitive deficits often observed in this AD mouse model.

    “These data suggest that both pTau accumulation and increased gliosis observed in 9m-PS19 mice may play a role in neurodegeneration within the DG, potentially contributing to the cognitive deficits often observed in this AD mouse model (Yoshiyama et al. 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yoshiyama et al. 2007 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Adult neurogenesis within the DG is well-established in rodents.

    “since adult neurogenesis within the DG is well-established in rodents (Altman & Das 1965).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Altman & Das 1965 source

  • May combine two claims.

    Premisecitation

    In the human cohort, there was a stepwise increase in cortical 6S-CS isomer expression from non-demented Braak 0-II to non-demented Braak III/IV subjects, and a second increase from non-demented Braak III/IV to demented Braak V/VI subjects.

    “In our human cohort, we observed a stepwise increase in cortical 6S-CS isomer expression from non-demented Braak 0-II to non-demented Braak III/IV subjects, as well as a second increase from non-demented Braak III/IV to demented Braak V/VI subjects (Logsdon et al. 2022).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Logsdon et al. 2022

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

  • May combine two claims.

    Interpretationown data

    9m-PS19 mice exhibit increased neurodegeneration within the DG subregion of the hippocampus in association with accumulated pTau, elevated gliosis, and shifts in CS-GAG sulfation patterning.

    “Overall, we conclude that 9m-PS19 mice exhibit increased neurodegeneration within the DG subregion of the hippocampus in association with accumulated pTau, elevated gliosis, and shifts in CS-GAG sulfation patterning.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The increase in 2S6S-CS isomer may form pericellular matrix coats and interact similarly with enmeshed neurons, thus providing important clues as to how the brain may attempt to regenerate neural circuitry in response to neurodegeneration.

    “Regardless of submatrix expression, we predict that the increase in 2S6S-CS isomer may for pericellular matrix coats and interact similarly with enmeshed neurons, thus providing important clues as to how the brain may attempt to regenerate neural circuitry in response to neurodegeneration.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The bulk LC-MS/MS technique may also be detecting changes in CS sulfation patterns of non-PNN matrices in the brain, including the interstitial matrix and so-called 'glial-scarring' deposits.

    “A second limitation to this study is that our bulk LC-MS/MS technique may also be detecting changes in CS sulfation patterns of non-PNN matrices in the brain, including the interstitial matrix and so-called ‘glial-scarring’ deposits.”
    Quote in the paperNot a substantial claim
54 of 54

  • The paper relies on this without support.

    Mouse models of tauopathy can translate the changes in PNNs observed in human AD patients.

    “To address the lack of appropriate mouse models capable of translating the changes in PNNs observed in human AD patients, we performed a thorough analysis between two distinct mouse models of tauopathy”
1 of 1

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.

  • Tg2652 PNNs are described as stable despite significant increases

    Minor

    The abstract says Tg2652 mice have stable PNN structures, but the results report significant increases in both the PNN CS-GAG marker and aggrecan core protein. The stated absence of PNN changes is inconsistent with those results.

1 of 1

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Authors
Logsdon, A. F., Foresi, B., Hu, S. J., Quah, E., Meuret, C. J., Le, J. P., Hendrickson, A. S., Redford, I. K., Kumar, A., Phan, B. A., Doan, T. P., Noonan, C., Hendricks, N. E., Wheeler, J. M., Kraemer, B. C., & Alonge, K. M.
Affiliations
  • University of Washington (US)
  • Northeast Ohio Medical University (US)
  • Oregon Health & Science University (US)
  • University of Southern California (US)
  • VA Puget Sound Health Care System (US)
Corresponding author
Alonge, Kimberly M.
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2024-02-05
Volume
168
Issue
9
Pages
1923-1936
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.16067
PMC
PMC11298576
OpenAlex
W4391612340
Semantic Scholar
36277bbeb7d749c460b5b1486a0e8c887ea8d09f
Cited by
16
References
51
Citations by year
2026: 3 · 2025: 7 · 2024: 6
FWCI
3.76
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institute on Aging (P30 AG066509, R01 AG066211, R21 AG074152, T32 AG052354)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK017047)
  • National Institute of Allergy and Infectious Diseases (DP2 AI171150)
  • U.S. Department of Defense (AZ210089)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
perineuronal nets, tauopathy, Alzheimer's disease, hyperphosphorylated tau, chondroitin sulfate, glycosaminoglycan sulfation, gliosis, neurodegeneration, extracellular matrix, aggrecan, hippocampus, transgenic mouse model
MeSH terms
Alzheimer Disease, Animals, Brain, Extracellular Matrix, Female, Gliosis, Glycosylation, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, tau Proteins, Neurodegenerative Diseases, Tauopathies, Mice

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-24.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-24.

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