Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress
Open accessAbstract
In Alzheimer's disease (AD), different types of neurons and different brain areas show differential patterns of vulnerability towards neurofibrillary degeneration, which provides the basis for a highly predictive profile of disease progression throughout the brain that now is widely accepted for neuropathological staging. In previous studies we could demonstrate that in AD cortical and subcortical neurons are constantly less frequently affected by neurofibrillary degeneration if they are enwrapped by a specialized form of the hyaluronan-based extracellular matrix (ECM), the so called 'perineuronal net' (PN). PNs are basically composed of large aggregating chondroitin sulphate proteoglycans connected to a hyaluronan backbone, stabilized by link proteins and cross-linked via tenascin-R (TN-R). Under experimental conditions in mice, PN-ensheathed neurons are better protected against iron-induced neurodegeneration than neurons without PN. Still, it remains unclear whether these neuroprotective effects are directly mediated by the PNs or are associated with some other mechanism in these neurons unrelated to PNs. To identify molecular components that essentially mediate the neuroprotective aspect on PN-ensheathed neurons, we comparatively analysed neuronal degeneration induced by a single injection of FeCl3 on four different mice knockout strains, each being deficient for a different component of PNs. Aggrecan, link protein and TN-R were identified to be essential for the neuroprotective properties of PN, whereas the contribution of brevican was negligible. Our findings indicate that the protection of PN-ensheathed neurons is directly mediated by the net structure and that both the high negative charge and the correct interaction of net components are essential for their neuroprotective function.
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Written from the paper’s full text.
TL;DR
Using FeCl3 injection into mouse barrel cortex, this study shows that perineuronal nets (PNs) directly protect neurons against iron-induced oxidative degeneration, and that aggrecan, link protein HAPLN1, and tenascin-R are essential for this protection. Brevican contributes little to the neuroprotective effect, although its loss increases lesion spread.
Key findings
- In wild-type mice, PN-ensheathed neurons were about 10% of all neurons, with about 49% of them containing parvalbumin; PN-associated neurons were less frequently degenerated than neurons without PN after FeCl3 injection.
- Neuroprotection was lost in HAPLN1−/− and TN-R−/− mice; aggrecan-deficient (ACAN+/−) mice showed partial loss depending on whether PNs were detected with WFA or anti-aggrecan HAG, while brevican knockout (BCAN−/−) mice retained significant protection.
- All knockout strains had larger lesions than wild type: TN-R−/− showed the most extensive degeneration with a radius of about 1500 μm, whereas HAPLN1−/−, ACAN+/−, and BCAN−/− averaged between 1300 and 1350 μm; control NaCl injections produced only marginal lesions with maximum radii of 200 μm.
- After injury, aggrecan content increased in the iron-injected hemisphere in all tested lines, significantly by 45% in BCAN−/− and 67% in HAPLN1−/− mice; ACAN+/− mice showed a 60% reduction in overall aggrecan content versus wild type.
Methods
- Four mouse knockout/deficient strains were compared with wild type: aggrecan (ACAN+/−), brevican (BCAN−/−), tenascin-R (TN-R−/−), and link protein 1 (HAPLN1−/−).
- Three-month-old mice received a single 0.2 μl injection of 20 mM FeCl3 into the barrel field cortex and were analyzed 24 h later; five animals per group were used, with n=3 for NaCl controls.
- Degenerating neurons were detected by Fluoro-Jade B, anti-caspase-3, or anti-phosphoS139 H2AX, combined with PN labeling via WFA or anti-aggrecan HAG and NeuN; aggrecan content was assessed by western blotting after chondroitinase ABC digestion.
Limitations
- The paper does not state a limitations section. Evident from the text: the aggrecan model is heterozygous (ACAN+/−), not a complete knockout, so residual aggrecan function may remain.
- Evident from the text: sample sizes were small (five animals per group; n=3 for controls), and lesion-size differences among the knockout strains were not statistically significant.
- Evident from the text: analyses were performed at a single time point (24 h after FeCl3 injection) in mice, so longer-term degeneration and recovery are not addressed.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 42 cited sources checked · 0 supported · 0 flagged
- Findingown data
Aggrecan is essential for the neuroprotective properties of perineuronal nets.
“Our data show that PN detected by the aggrecan antibody HAG in mice heterozygous deficient for aggrecan (ACAN+/−), have lost their neuroprotective properties.”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
Brevican has a negligible contribution to the neuroprotective properties of perineuronal nets.
“whereas the contribution of brevican was negligible.”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
Tenascin-R is essential for the neuroprotective properties of perineuronal nets.
“Our present data show that TN-R is also essential for the neuroprotective properties of PNs.”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
Link protein HAPLN1 is essential for the neuroprotective properties of perineuronal nets.
“Our experiments show that PNs lacking HAPLN1 have completely lost their neuroprotective properties.”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
In BCAN−/− mice, PN-associated neurons with PV detected by WFA as well as HAG were significantly more frequently affected than those without PV.
“In BCAN−/− mice, PN-associated neurons with PV detected by WFA as well as HAG were even significantly more frequently affected than those without PV.”
Quote in the paperSubstantial claim
- Findingown data
In TN-R−/− mice, differences in vulnerability between neurons with and without PN are abolished completely.
“Differences in vulnerability between neurons with and without PN were abolished completely in mice lacking either the link protein 1 (HAPLN-1−/−) (Figure 6d) or tenascin-R (TN-R−/−) (Figure 6e).”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
The vast majority of degenerating neurons detected by any of the three methods were devoid of PNs.
“The vast majority of degenerating neurons, detected with any of these methods, were devoid of PNs (Figure 4).”
Quote in the paperSubstantial claim - Findingown data
In HAPLN1−/− mice, aggrecan content is increased by 67% after iron injection.
“Here, the content of aggrecan is increased by 45% (BCAN−/−) and 67% (HAPLN1−/−).”
Quote in the paperNot a substantial claim - Findingown data
Control injections with 0.9% NaCl produce only marginal lesions with maximum degeneration radii of 200 μm.
“Control injections with 0.9% NaCl revealed only marginal lesions with maximum degeneration radii of 200 μm (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
In BCAN−/− mice, aggrecan content is increased by 45% after iron injection.
“Here, the content of aggrecan is increased by 45% (BCAN−/−) and 67% (HAPLN1−/−).”
Quote in the paperNot a substantial claim - Findingown data
In HAPLN1−/− mice, differences in vulnerability between neurons with and without PN are abolished completely.
“Differences in vulnerability between neurons with and without PN were abolished completely in mice lacking either the link protein 1 (HAPLN-1−/−) (Figure 6d) or tenascin-R (TN-R−/−) (Figure 6e).”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
No increased protection of PV-associated net-wearing neurons could be observed.
“As summarized in Figures 6a1–e1, no increased protection of PV-associated net-wearing neurons could be observed.”
Quote in the paperNot a substantial claim - Findingown data
In aggrecan-deficient mice (ACAN+/−), neurons ensheathed by a PN visualized with WFA are less frequently affected by degeneration than neurons without PN.
“In aggrecan-deficient mice (ACAN+/−), neurons ensheathed by a PN, visualized with WFA, were also less frequently affected by degeneration compared with neurons without PN (Figure 6b).”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
In ACAN+/− mice, overall aggrecan content is reduced by 60% compared with WT.
“Here, the overall content of aggrecan is reduced by 60% compared with the analysed tissue of WT mice.”
Quote in the paperNot a substantial claim - Findingown data
All transgenic mouse strains deficient in a PN component show significantly larger FeCl3-induced brain lesions than wild-type mice.
“Quantification of the lesion size, however, clearly showed that all transgenic mice strains showed significantly larger degeneration than wild-type mice (Figure 3f).”
Quote in the paperSubstantial claim - Findingown data
In aggrecan-deficient mice (ACAN+/−), the difference in degeneration between neurons with and without PN disappears when aggrecan immunocytochemistry (HAG) is used for PN detection.
“This difference disappeared, however, when aggrecan immunocytochemistry (HAG) was used for detection of PNs.”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Findingown data
TN-R deficiency mediates the most extensive degeneration, with a lesion radius of about 1500 μm.
“A lack of tenascin-R (TN-R−/−) mediated the most extensive degeneration with a radius of about 1500 μm of the affected cross-sectional area.”
Quote in the paperSubstantial claim - Findingown data
Western blot analysis with anti-aggrecan antibody AB1031 revealed a single band at ∼450 kDa in injured and uninjured hemispheres.
“Western blot analysis with the anti-aggrecan antibody AB1031 revealed a single band at ∼450 kDa in injured and uninjured hemispheres (Figure 7a).”
Quote in the paperNot a substantial claim - Findingown data
In brevican knockout mice (BCAN−/−), PN-associated neurons are significantly less frequently affected by degeneration than neurons without PN, independent of PN detection method.
“In brevican knockout mice (BCAN−/−), PN-associated neurons were significantly less frequently affected by degeneration than neurons without PN. This effect was independent of the detection method of PNs (Figure 6c).”
Quote in the paperSubstantial claim- Rests on an assumption: Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
- Premisecitation
In Alzheimer's disease, cortical and subcortical neurons enwrapped by a perineuronal net are less frequently affected by neurofibrillary degeneration than neurons without a perineuronal net.
“In previous studies we could demonstrate that in AD cortical and subcortical neurons are constantly less frequently affected by neurofibrillary degeneration if they are enwrapped by a specialized form of the ECM, the so-called PN.2, 3”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Bruckner G, Hausen D, Hartig W, Drlicek M, Arendt T, Brauer K . Cortical areas abundant in extracellular matrix chondroitin sulphate proteoglycans are less affected by cytoskeletal changes in Alzheimer's disease. Neuroscience 1999; 92: 791–805. source
Not checked in the free run.
- cites [3] Morawski M, Bruckner G, Jager C, Seeger G, Matthews RT, Arendt T . Involvement of perineuronal and perisynaptic extracellular matrix in Alzheimer's disease neuropathology. Brain Pathol 2012; 22: 547–561. source
Not checked in the free run.
- Interpretationown data
The protection of PN-ensheathed neurons is directly mediated by the net structure.
“Our findings indicate that the protection of PN-ensheathed neurons is directly mediated by the net structure”
Quote in the paperSubstantial claim - Premisecitation
Under experimental conditions in mice, PN-ensheathed neurons are better protected against iron-induced neurodegeneration than neurons without PN.
“We could show that net-associated neurons were less severely affected by degeneration than neurons without PNs.28”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Suttkus A, Rohn S, Jäger C, Arendt T, Morawski M . Neuroprotection against iron-induced cell death by perineuronal nets—An in vivo analysis of oxidative stress. Am J Neurodegener Dis 2012; 1: 122–129.
Not checked in the free run.
- Interpretationown data
Other matrix compounds providing WFA binding sites might partially compensate for the loss of aggrecan in ACAN+/− mice.
“This might indicate that other matrix compounds providing binding sites for WFA might partially compensate for the loss of aggrecan.”
Quote in the paperNot a substantial claim - Interpretationreasoning
WFA binding, indicating the presence of highly charged anionic binding sites, provides a signature for the neuroprotective properties of perineuronal nets.
“In addition, it might show that WFA binding, indicating the presence of highly charged anionic binding sites, provides a signature for the neuroprotective properties of PNs.”
Quote in the paperNot a substantial claim - Interpretationown data
The correct interaction of net components to form a stable barrier against ions is an essential factor for the neuroprotective properties of perineuronal nets against iron-induced cell death.
“both the high negative charge and the correct interaction of net components to form a stable barrier against ions are essential factors for their neuroprotective properties”
Quote in the paperSubstantial claim - Study design and conductown data
Rare cases of PN-ensheathed degenerating neurons ruled out systemic bias in accessibility of the detection dye to neurons with versus without PN.
“Still these rare cases, as exemplified in Figure 4, clearly ruled out any systemic bias with respect to accessibility of the detection dye to neurons ensheathed by PN compared with neurons without PN.”
Quote in the paperSubstantial claim - Premiseown data
In normal-aged brain and AD, neurons ensheathed by a PN are less frequently affected by lipofuscin accumulation than neurons without a net.
“we previously observed that both in normal-aged brain and AD neurons ensheathed by a PN are less frequently affected by lipofuscin accumulation than neurons without a net.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [22] Morawski M, Bruckner MK, Riederer P, Bruckner G, Arendt T . Perineuronal nets potentially protect against oxidative stress. Exp Neurol 2004; 188: 309–315. source
Not checked in the free run.
- cites [23] Morawski M, Reinert T, Brückner G, Wagner FE, Arendt TH, Tröger W . The binding of iron to perineuronal nets: a combined nuclear microscopy and Mössbauer study. Hyperfine Interact 2004; 159: 285–291. source
Not checked in the free run.
- cites [29] Sohal RS, Brunk UT . Lipofuscin as an indicator of oxidative stress and aging. Adv Exp Med Biol 1989; 266: 17–26.
Not checked in the free run.
- cites [30] Canas N, Valero T, Villarroya M, Montell E, Verges J, Garcia AG et al. Chondroitin sulfate protects SH-SY5Y cells from oxidative stress by inducing heme oxygenase-1 via phosphatidylinositol 3-kinase/Akt. J Pharmacol Exp Ther 2007; 323: 946–953. source
Not checked in the free run.
- cites [31] Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK et al. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proc Natl Acad Sci USA 2013; 110: 9130–9135. source
Not checked in the free run.
- Interpretationown data
The highly negative charge of aggrecan is the main aspect of the protective feature of perineuronal nets.
“This highly negative charge could be the main aspect of the protective feature.”
Quote in the paperSubstantial claim - Premisecitation
ACAN+/− mice are aggrecan-deficient.
“heterozygote aggrecan-deficient (ACAN+/−) mice”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [36] Giamanco KA, Morawski M, Matthews RT . Perineuronal net formation and structure in aggrecan knockout mice. Neuroscience 2010; 170: 1314–1327. source
Not checked in the free run.
- cites [43] Giamanco KA, Matthews RT . Deconstructing the perineuronal net: cellular contributions and molecular composition of the neuronal extracellular matrix. Neuroscience 2012; 218: 367–384. source
Not checked in the free run.
- cites [54] Watanabe H, Nakata K, Kimata K, Nakanishi I, Yamada Y . Dwarfism and age-associated spinal degeneration of heterozygote cmd mice defective in aggrecan. Proc Natl Acad Sci USA 1997; 94: 6943–6947. source
Not checked in the free run.
- Interpretationreasoning
A strong connection of CSPGs to hyaluronan seems to be an essential factor for the neuroprotective function of perineuronal nets.
“Therefore, a strong connection of the CSPGs to hyaluronan seems to be an essential factor.”
Quote in the paperSubstantial claim - Interpretationreasoning
The reduced lipofuscin accumulation in PN-ensheathed neurons suggests a neuroprotective function of PNs against neurodegeneration induced by oxidative stress.
“As lipofuscin is an intralysosomal pigment composed of cross-linked proteins and lipids generated by iron-catalysed oxidative processes, this finding suggests a neuroprotective function of PNs against neurodegeneration induced by oxidative stress.22, 23, 29, 30, 31”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [22] Morawski M, Bruckner MK, Riederer P, Bruckner G, Arendt T . Perineuronal nets potentially protect against oxidative stress. Exp Neurol 2004; 188: 309–315. source
Not checked in the free run.
- cites [23] Morawski M, Reinert T, Brückner G, Wagner FE, Arendt TH, Tröger W . The binding of iron to perineuronal nets: a combined nuclear microscopy and Mössbauer study. Hyperfine Interact 2004; 159: 285–291. source
Not checked in the free run.
- cites [29] Sohal RS, Brunk UT . Lipofuscin as an indicator of oxidative stress and aging. Adv Exp Med Biol 1989; 266: 17–26.
Not checked in the free run.
- cites [30] Canas N, Valero T, Villarroya M, Montell E, Verges J, Garcia AG et al. Chondroitin sulfate protects SH-SY5Y cells from oxidative stress by inducing heme oxygenase-1 via phosphatidylinositol 3-kinase/Akt. J Pharmacol Exp Ther 2007; 323: 946–953. source
Not checked in the free run.
- cites [31] Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK et al. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proc Natl Acad Sci USA 2013; 110: 9130–9135. source
Not checked in the free run.
- Interpretationown data
Neuroprotection of neurons ensheathed by a perineuronal net against iron-induced cell death is directly mediated by the perineuronal net.
“the neuroprotection of neurons ensheathed by a PN against iron-induced cell death is directly mediated by the PN”
Quote in the paperSubstantial claim - Interpretationcitation
A facilitated diffusion of dissociated FeCl3 due to the lack of PN components most likely accounts for the increased spreading of degeneration in knockout mice.
“On the background of previous reports on the contribution of lecticans40, 41 and TN-R42 to the diffusion and hydration properties of the neural ECM, a facilitated diffusion of dissociated FeCl3 due to the lack of PN components most likely accounts for these effects.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [40] Sykova E . Extracellular space volume and geometry of the rat brain after ischemia and central injury. Adv Neurol 1997; 73: 121–135.
Not checked in the free run.
- cites [41] Hrabetova S, Masri D, Tao L, Xiao F, Nicholson C . Calcium diffusion enhanced after cleavage of negatively charged components of brain extracellular matrix by chondroitinase ABC. J Physiol 2009; 587: 4029–4049. source
Not checked in the free run.
- cites [42] Sykova E, Vorisek I, Mazel T, Antonova T, Schachner M . Reduced extracellular space in the brain of tenascin-R- and HNK-1-sulphotransferase deficient mice. Eur J Neurosci 2005; 22: 1873–1880. source
Not checked in the free run.
- Interpretationreasoning
TN-R, by forming stable aggregates, has a relevant part in mediating a protective aspect of perineuronal nets.
“This leads to the assumption that TN-R, by way of forming stable aggregates, has a relevant part in mediating a protective aspect of the PNs.”
Quote in the paperSubstantial claim - Premisereasoning
Aggrecan interacting with hyaluronan mainly contributes to the polyanionic character of the perineuronal net.
“Thus, aggrecan interacting with hyaluronan, also highly negatively charged, mainly contributes to the polyanionic character of the PN.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [10] Morawski M, Bruckner G, Arendt T, Matthews RT . Aggrecan: Beyond cartilage and into the brain. Int J Biochem Cell Biol 2012; 44: 690–693. source
Not checked in the free run.
- cites [45] Yamaguchi Y . Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci 2000; 57: 276–289. source
Not checked in the free run.
- Interpretationcitation
The content of aggrecan in ACAN+/− perineuronal nets is reduced below a critical level not sufficient to exert neuroprotective effects.
“Most likely, the content of aggrecan in these PNs is reduced below a critical level, which is not sufficient to exert the neuroprotective effects.44”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Matthews RT, Kelly GM, Zerillo CA, Gray G, Tiemeyer M, Hockfield S . Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets. J Neurosci 2002; 22: 7536–7547. source
Not checked in the free run.
- Interpretationown data
The high negative charge of the perineuronal net is an essential factor for its neuroprotective properties against iron-induced cell death.
“both the high negative charge and the correct interaction of net components to form a stable barrier against ions are essential factors for their neuroprotective properties”
Quote in the paperSubstantial claim - Premisecitation
Sulphate groups on GAGs together with negatively charged hyaluronic acid generate a highly polyanionic microenvironment around PN-ensheathed neurons.
“Sulphate groups attached to these GAGs in concert with the negatively charged hyaluronic acid generate a highly polyanionic microenvironment around PN-ensheathed neurons.20, 21”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [20] Bruckner G, Brauer K, Hartig W, Wolff JR, Rickmann MJ, Derouiche A et al. Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain. Glia 1993; 8: 183–200. source
Not checked in the free run.
- cites [21] Murakami T, Tsubouchi M, Tubouchi Y, Taguchi T, Ohtsuka A . The occurrence of neurons with strongly negatively charged surface coats in mammalian, avian, reptilian, amphibian and piscine brains. Acta Med Okayama 1994; 48: 195–197.
Not checked in the free run.
- Premisecitation
HAPLN1−/− mice are link protein-deficient.
“link protein-deficient (HAPLN1−/−) mice”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Carulli D, Pizzorusso T, Kwok JC, Putignano E, Poli A, Forostyak S et al. Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 2010; 133: 2331–2347. source
Not checked in the free run.
- cites [56] Czipri M, Otto JM, Cs-Szabo G, Kamath RV, Vermes C, Firneisz G et al. Genetic rescue of chondrodysplasia and the perinatal lethal effect of cartilage link protein deficiency. J Biol Chem 2003; 278: 39214–39223. source
Not checked in the free run.
- May combine two claims. 8
- Classified as probably not a substantial claim. 7
May combine two claims.
FindingcitationIn wild-type mice, PN-ensheathed neurons amount to about 10% of all neurons, with about half (49%) containing parvalbumin.
“In wild-type animals, PN-ensheathed neurons amounted to about 10% of all neurons, with about half of them (49%) containing PV.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nowicka et al.35 Nowicka D, Soulsby S, Skangiel-Kramska J, Glazewski S . Parvalbumin-containing neurons, perineuronal nets and experience-dependent plasticity in murine barrel cortex. Eur J Neurosci 2009; 30: 2053–2063. source
Not checked in the free run.
May combine two claims.
Findingown dataHAPLN1−/−, ACAN+/−, and BCAN−/− mice have average lesion radii between 1300 and 1350 μm, with no significant differences among them.
“Somewhat smaller dimensions of degeneration were observed in mice lacking link protein 1 (HAPLN1−/−), aggrecan (ACAN+/−) or brevican (BCAN−/−) with average radii of the lesion between 1300 and 1350 μm. However, no significant differences could be measured.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNet-associated neurons and net-associated PV-positive neurons are significantly reduced in number in HAPLN1−/− and TN-R−/− mice.
“In contrast, net-associated neurons as well as net-associated PV positive neurons were significantly reduced in number in HAPLN1−/− and TN-R−/− mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe lack of brevican and the deficit of aggrecan have no effect on the presence of PN-ensheathed neurons.
“The lack of brevican as well as the deficit of aggrecan had no effects on the presence of PN-ensheathed neurons.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe ratio of PN-associated neurons with and without PV is shifted only in TN-R−/− mice, with a significant reduction of PV-containing PN-ensheathed neurons.
“The ratio of PN-associated neurons with and without PV was only shifted in TN-R−/− mice, with a significant reduction of PV containing PN-ensheathed neurons.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAggrecan content is higher in iron-injected hemispheres than in contralateral uninjected hemispheres for all tested mouse lines, with significant differences in mice lacking brevican or HAPLN1.
“A comparative quantification with TINA software (Raytest, Straubenhardt, Germany) revealed higher contents of aggrecan in iron-injected hemispheres for all tested mouse lines, with significant differences in mice lacking brevican or HAPLN1 (Figure 7b).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHAPLN1 and TN-R are essential for the neuroprotective function of perineuronal nets.
“Further, our data indicate that the two matrix components, HAPLN1 and TN-R, are also essential for the neuroprotective function of PNs.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationPerineuronal nets are composed of chondroitin sulphate proteoglycans, including lecticans, phosphacan, hyaluronan, tenascin-R and link proteins.
“PNs are composed of chondroitin sulphate proteoglycans (CSPGs), including lecticans (aggrecan, brevican, neurocan and versican), phosphacan and hyaluronan, TN-R and link proteins (cartilage link protein Crtl-1/HAPLN-1 and brain link protein Bral2/HAPLN-4).11, 12, 13, 14”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [11] Asher RA, Scheibe RJ, Keiser HD, Bignami A . On the existence of a cartilage-like proteoglycan and link proteins in the central nervous system. Glia 1995; 13: 294–308. source
Not checked in the free run.
- cites [12] Bekku Y, Su WD, Hirakawa S, Fassler R, Ohtsuka A, Kang JS et al. Molecular cloning of Bral2, a novel brain-specific link protein, and immunohistochemical colocalization with brevican in perineuronal nets. Mol Cell Neurosci 2003; 24: 148–159. source
Not checked in the free run.
- cites [13] Carulli D, Pizzorusso T, Kwok JC, Putignano E, Poli A, Forostyak S et al. Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 2010; 133: 2331–2347. source
Not checked in the free run.
- cites [14] Bekku Y, Saito M, Moser M, Fuchigami M, Maehara A, Nakayama M et al. Bral2 is indispensable for the proper localization of brevican and the structural integrity of the perineuronal net in the brainstem and cerebellum. J Comp Neurol 2011; 520: 1721–1736. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningBoth the high negative charge and the correct interaction of net components are essential for the neuroprotective function of perineuronal nets.
“both the high negative charge and the correct interaction of net components are essential for their neuroprotective function.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataThree independent methods were used to detect degenerating neurons: Fluoro-Jade B staining, a caspase-3 antibody, and an antibody against H2AX.
“Three independent methods were used to detect degenerating neurons, namely Fluoro-Jade B staining, a caspase-3 antibody and an antibody against H2AX in combination with histochemical labelling of the net structures.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationIron ions are involved in generating oxidative stress.
“the polyanionic components might also interact with ions of potential pathophysiological relevance such as iron ions involved in generating oxidative stress.20, 22, 26, 27”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [20] Bruckner G, Brauer K, Hartig W, Wolff JR, Rickmann MJ, Derouiche A et al. Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain. Glia 1993; 8: 183–200. source
Not checked in the free run.
- cites [22] Morawski M, Bruckner MK, Riederer P, Bruckner G, Arendt T . Perineuronal nets potentially protect against oxidative stress. Exp Neurol 2004; 188: 309–315. source
Not checked in the free run.
- cites [26] Hartig W, Singer A, Grosche J, Brauer K, Ottersen OP, Bruckner G . Perineuronal nets in the rat medial nucleus of the trapezoid body surround neurons immunoreactive for various amino acids, calcium-binding proteins and the potassium channel subunit Kv3.1b. Brain Res 2001; 899: 123–133. source
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- cites [27] Reinert T, Morawski M, Arendt T, Butz T . Quantitative microanalysis of perineuronal nets in brain tissue. Nucl Instrum Methods Phys Res Sect B 2003; 210: 395–400. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPhosphoS139 H2AX is a well-established marker for double-stranded DNA breaks.
“phosphoS139 H2AX, a well-established marker for double-stranded DNA breaks”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM . DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998; 273: 5858–5868. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFluoro-Jade B specifically stains degenerating neurons by binding to a currently unknown, most likely poly-amine, basic substance in the neuron.
“Fluoro-Jade B as anionic dye specifically stains degenerating neurons by binding to a currently unknown, most likely a poly-amine, basic substance in the neuron.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [59] Ohk TG, Yoo KY, Park SM, Shin BN, Kim IH, Park JH et al. Neuronal damage using fluoro-jade B histofluorescence and gliosis in the striatum after various durations of transient cerebral ischemia in gerbils. Neurochem Res 2012; 37: 826–834. source
Not checked in the free run.
- cites [60] Schmued LC, Hopkins KJ . Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 2000; 874: 123–130. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBCAN−/− mice are brevican knockout.
“brevican knockout mice (BCAN−/−) mice”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [32] Brakebusch C, Seidenbecher CI, Asztely F, Rauch U, Matthies H, Meyer H et al. Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol Cell Biol 2002; 22: 7417–7427. source
Not checked in the free run.
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Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationTN-R−/− mice are TN-R knockout.
“TN-R knockout mice (TN-R−/−)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [33] Weber P, Bartsch U, Rasband MN, Czaniera R, Lang Y, Bluethmann H et al. Mice deficient for tenascin-R display alterations of the extracellular matrix and decreased axonal conduction velocities in the CNS. J Neurosci 1999; 19: 4245–4262. source
Not checked in the free run.
- cites [34] Bruckner G, Grosche J, Schmidt S, Hartig W, Margolis RU, Delpech B et al. Postnatal development of perineuronal nets in wild-type mice and in a mutant deficient in tenascin-R. J Comp Neurol 2000; 428: 616–629. source
Not checked in the free run.
The paper relies on this without support.
Deficiency of a single perineuronal net component in the knockout strains does not itself alter neuronal vulnerability to iron-induced degeneration apart from its effect on the perineuronal net.
“The constitutive deficiency of defined molecular net components had some phenotypic effects on the appearance but not on the number of PNs in all tested mouse strains.”
The paper relies on this without support.
Aggrecan is the main proteoglycan component of the perineuronal net.
“the main proteoglycan component of the PN”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ADAMTS1 is elevated in Down's syndrome with neurodegeneration and Alzheimer's disease, and it is a potential neuroprotective or neuroinflammatory gene.
“ADAMTS1 is elevated in Down’s syndrome with neurodegeneration and Alzheimer’s disease86, and it is a potential neuroprotective gene87–89 or a neuroinflammatory gene important to microglial response90.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [87]
The CS-side chains of PNNs mediate its neuroprotective effects.
“These results lend further support to the idea that the CS-side chains of PNNs mediate its neuroprotective effects.”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Suttkus et al., 2014
Genetic reduction of aggrecan resulted in reduced neuroprotective effects.
“Genetic reduction of aggrecan, which has the highest number of CS-side chains and presumably the largest negative charge, resulted in reduced neuroprotective effects (Suttkus et al., 2014).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Suttkus et al., 2014
PNN components such as aggrecan, tenascin-R, and link proteins are essential for protection from oxidative stress.
“In particular, PNN components such as aggrecan, tenascin-R, and link proteins are essential for this protection (Suttkus et al., 2014).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Suttkus et al., 2014
PNNs may play a key role in protecting neurons from oxidative stress, such as that caused by a decrease of glutathione, a key brain antioxidant found to be decreased in schizophrenia.
“Emerging evidence shows that PNNs may play a key role in protecting neurons from oxidative stress, such as it may be caused by a decrease of glutathione, a key brain antioxidant found to be decreased in SZ (Cabungcal et al., 2013; Gawryluk et al., 2011; Suttkus et al., 2014).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Suttkus et al., 2014
Tenascins are a critical component of PNNs, which surround many of the neurons that are postsynaptic to adult-generated granule cells.
“Studies suggest that tenascins are a critical component of PNNs (Suttkus et al., 2014), which surround many of the neurons that are postsynaptic to adult-generated granule cells.”
From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Suttkus et al., 2014
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.
PN counts described as unchanged but reduced in two strains
MinorThe Results first state that the deficiencies affected PN appearance but not PN number in any tested strain. Later, they report significantly fewer net-associated neurons in HAPLN1−/− and TN-R−/− mice.
“The constitutive deficiency of defined molecular net components had some phenotypic effects on the appearance but not on the number of PNs in all tested mouse strains.”
“In contrast, net-associated neurons as well as net-associated PV positive neurons were significantly reduced in number in HAPLN1−/− and TN-R−/− mice.”
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Alzheimer Disease Genetics Consortium (ADGC), Kunkle, B. W., The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0358-2 · Cited by 2,946 · see citing works
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Neuronal Pentraxin 2 Binds PNNs and Enhances PNN Formation
Van’t Spijker, H. M., Rowlands, D., Rossier, J., Haenzi, B., Fawcett, J. W., & Kwok, J. C. F. (2019) · Neural Plasticity · doi:10.1155/2019/6804575 · Cited by 31 · see citing works
- Authors
- Suttkus, A., Rohn, S., Weigel, S., Glöckner, P., Arendt, T., & Morawski, M.
- Affiliations
- Leipzig University (DE)
- SUNY Upstate Medical University (US)
- Corresponding author
- Arendt, T
- Venue
- Cell Death & Disease
- Published
- 2014-03-13
- Volume
- 5
- Issue
- 3
- Pages
- e1119-e1119
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3973247
- OpenAlex
- W2022932966
- Cited by
- 168
- References
- 59
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 9 · 2023: 12 · 2022: 20 · 2021: 13 · 2020: 12 · 2019: 12 · 2018: 18 · 2017: 11 · 2016: 10 · 2015: 12 · 2014: 14
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Qucosa (Saxon State and University Library Dresden) (submittedVersion, other-oa)
- Funders
- European Commission
- Deutsche Forschungsgemeinschaft (GRK 1097, Mo2249/2-1)
- Freistaat Sachsen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- perineuronal nets, aggrecan, link protein, tenascin-R, brevican, oxidative stress, neuroprotection, Alzheimer's disease, neurofibrillary degeneration, hyaluronic acid, extracellular matrix, chondroitin sulfate proteoglycans, knockout mice
- MeSH terms
- Proteoglycan Link Protein, Animals, Brain, Chlorides, Chondroitin Sulfates, Extracellular Matrix, Female, Ferric Compounds, Genotype, Hyaluronic Acid, Male, Mice, Inbred C57BL, Nerve Degeneration, Neurons, Phenotype, Proteoglycans, Extracellular Matrix Proteins, Mice, Knockout, Oxidative Stress, Tenascin, Mice, Aggrecans, Brevican
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 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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.
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