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Cited by 138Alzheimer's disease research and treatmentsMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

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Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology

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Yang, Sujeong, Cacquevel, Matthias, Saksida, Lisa M., Bussey, Timothy J., Schneider, Bernard L., Aebischer, Patrick, Melani, Riccardo, Pizzorusso, Tommaso, Fawcett, James W., Spillantini, Maria Grazia·2015·Experimental Neurology
DOI 10.1016/j.expneurol.2014.11.013PMC PMC4353684
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Abstract

Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders.

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Fig. 1 Temporal progression of OR memory deficit in Tg P301S mice. A. Brain sections from 1 to 3 month-old P301S mice were stained with anti-hyperphosphorylated tau antibody AT8. Tau hyperphosphorylation was visualized by AT8 in the PRh of P301S mice. The PRh at the bregma − 1.82 mm is shown in a coronal brain section image modified from brain atlas (Paxinos et al., 2001). In 3 month-old mice tau immunostaining appeared more localized in cell bodies compared to 1 month-old mice. No staining was present in control brain (data not shown) B. Brains from P301S mice and age-matched control (C57BL/6S) were immunostained with NeuN antibody. NeuN-positive neurons were counted by stereology quantification. The neuronal cell loss in the PRh was significant in 3 month-old P301S mice compared to controls (WT n = 5, P301S n = 6, t-test, *p < 0.05) C. P301S mice showed the spontaneous OR memory deficit in the 3 h retention paradigm. The discrimination ratio represented as (novel − familiar object exploration time) / total exploration time. The OR memory deficit was significant in 3 month-old P301S mice compared to control mice (WT n = 6, P301S n = 10, t-test, **p < 0.01). The progression of the deficit was age-dependent in P301S mice. No deficit was present in 1 month-old mice compared to controls (WT n = 7, P301S n = 9), while in 2 month-old mice a deficit was present but it did not reach significance (WT n = 5, P301S n = 7). D. Three month-old P301S and control mice were subjected to a 1 min delay between sample and choice phases to determine whether possible visual problem in the P301S mice could have affected the results. Both P301S and control mice showed a similar strength of OR memory after a 1 min delay. E. In order to verify specificity of the transgenic effect on the deficit in the spontaneous OR task 3 and 7 month-old littermate control and heterozygous P301S mice (P301S Het) were tested to determine their memory for 3 h retention in the spontaneous OR task. Both control and P301S Het mice showed identical OR memory at 3 months of age (WT n = 6, P301S Het n = 7) but P301S Het mice showed a significant deficit compared to their littermate controls at 7 months of age (WT n = 8, P301S Het n = 7, t-test, **p < 0.01). Data are presented as mean ± SEM.
Fig. 1 Temporal progression of OR memory deficit in Tg P301S mice. A. Brain sections from 1 to 3 month-old P301S mice were stained with anti-hyperphosphorylated tau antibody AT8. Tau hyperphosphorylation was visualized by AT8 in the PRh of P301S mice. The PRh at the bregma − 1.82 mm is shown in a coronal brain section image modified from brain atlas (Paxinos et al., 2001). In 3 month-old mice tau immunostaining appeared more localized in cell bodies compared to 1 month-old mice. No staining was present in control brain (data not shown) B. Brains from P301S mice and age-matched control (C57BL/6S) were immunostained with NeuN antibody. NeuN-positive neurons were counted by stereology quantification. The neuronal cell loss in the PRh was significant in 3 month-old P301S mice compared to controls (WT n = 5, P301S n = 6, t-test, *p < 0.05) C. P301S mice showed the spontaneous OR memory deficit in the 3 h retention paradigm. The discrimination ratio represented as (novel − familiar object exploration time) / total exploration time. The OR memory deficit was significant in 3 month-old P301S mice compared to control mice (WT n = 6, P301S n = 10, t-test, **p < 0.01). The progression of the deficit was age-dependent in P301S mice. No deficit was present in 1 month-old mice compared to controls (WT n = 7, P301S n = 9), while in 2 month-old mice a deficit was present but it did not reach significance (WT n = 5, P301S n = 7). D. Three month-old P301S and control mice were subjected to a 1 min delay between sample and choice phases to determine whether possible visual problem in the P301S mice could have affected the results. Both P301S and control mice showed a similar strength of OR memory after a 1 min delay. E. In order to verify specificity of the transgenic effect on the deficit in the spontaneous OR task 3 and 7 month-old littermate control and heterozygous P301S mice (P301S Het) were tested to determine their memory for 3 h retention in the spontaneous OR task. Both control and P301S Het mice showed identical OR memory at 3 months of age (WT n = 6, P301S Het n = 7) but P301S Het mice showed a significant deficit compared to their littermate controls at 7 months of age (WT n = 8, P301S Het n = 7, t-test, **p < 0.01). Data are presented as mean ± SEM.CC BY · PubMed Central
Fig. 2 AAV-P301S induced neurodegenerative tauopathy and OR memory deficit. A. Schematic illustration for AAV-P301S injection sites. Asterisks indicated the injection site. B. Immunostaining with AT8 antibody 2 months after the bi-lateral injections of AAV-P301S into the PRh of C57BL/6S mice. Dashed lines indicate the area of the PRh. Asterisks indicate the injection site. C. More abundant tau pathology in the PRh cortex was present compared to adjacent cortices. i) Labeling with AT8 antibody revealed the tauopathy-induced lesion on the PRh at bregma − 2.16 mm. ii) Adjacent regions such as the entorhinal cortex were not affected as much as PRh. iii) AT8-positive neurons and dendrites were present in the PRh. iv) Hyperphosphorylated tau deposits were also detected by PHF1 antibody. Scale bar, i: 500 μm, and ii–iv: 30 μm D. Immunostaining with NeuN antibody showed a significant neuronal cell loss in the PRh. AAV-fpmax injected mice (i–iii) displayed less neuronal damage and significantly more neurons compared to AAV-P301S injected mice (iv–vi). This was confirmed by stereological quantification (AAV-fpmax n = 3, AAV-P301S n = 5, t-test, **p < 0.01). Data are presented as mean ± SEM. E. AAV-fpmax (n = 12), AAV-TauWT (n = 13) and AAV-P301S (n = 12) injected mice were tested in the spontaneous OR task for 1 min or 3 h of memory retention. There was no difference between AAV-fpmax and AAV-P301S groups after a 1 min delay while AAV-P301S injected mice showed a significant impairment in OR memory following a 3 h delay. ANOVA followed by Tukey post-hoc test, *p < 0.05, **p < 0.01.
Fig. 2 AAV-P301S induced neurodegenerative tauopathy and OR memory deficit. A. Schematic illustration for AAV-P301S injection sites. Asterisks indicated the injection site. B. Immunostaining with AT8 antibody 2 months after the bi-lateral injections of AAV-P301S into the PRh of C57BL/6S mice. Dashed lines indicate the area of the PRh. Asterisks indicate the injection site. C. More abundant tau pathology in the PRh cortex was present compared to adjacent cortices. i) Labeling with AT8 antibody revealed the tauopathy-induced lesion on the PRh at bregma − 2.16 mm. ii) Adjacent regions such as the entorhinal cortex were not affected as much as PRh. iii) AT8-positive neurons and dendrites were present in the PRh. iv) Hyperphosphorylated tau deposits were also detected by PHF1 antibody. Scale bar, i: 500 μm, and ii–iv: 30 μm D. Immunostaining with NeuN antibody showed a significant neuronal cell loss in the PRh. AAV-fpmax injected mice (i–iii) displayed less neuronal damage and significantly more neurons compared to AAV-P301S injected mice (iv–vi). This was confirmed by stereological quantification (AAV-fpmax n = 3, AAV-P301S n = 5, t-test, **p < 0.01). Data are presented as mean ± SEM. E. AAV-fpmax (n = 12), AAV-TauWT (n = 13) and AAV-P301S (n = 12) injected mice were tested in the spontaneous OR task for 1 min or 3 h of memory retention. There was no difference between AAV-fpmax and AAV-P301S groups after a 1 min delay while AAV-P301S injected mice showed a significant impairment in OR memory following a 3 h delay. ANOVA followed by Tukey post-hoc test, *p < 0.05, **p < 0.01.CC BY · PubMed Central
Fig. 3 Removal of PNNs by ChABC treatment in Tg P301S mice. A. The sagittal brain atlas illustrates the injection levels of ChABC. Immunohistochemistry using WFA in P-nase (a–c) ChABC (a′–c′) injected Tg P301S mice at 2 weeks post-injection. It showed the extent of depletion of PNNs by ChABC treatment, indicated by the dotted line. B. Profiles of WFA-positive PNNs in the PRh of P301S mice at higher magnification following P-nase or ChABC injection. Scale bar, 50 μm C. Stereological analysis of WFA-positive neurons in the PRh of P301S mice following P-nase or ChABC injection. Data are presented as mean ± SEM. A significant decrease in WFA staining is caused by ChABC injection in Tg P301S mice (P-nase n = 6, ChABC n = 6, t-test, **p < 0.01).
Fig. 3 Removal of PNNs by ChABC treatment in Tg P301S mice. A. The sagittal brain atlas illustrates the injection levels of ChABC. Immunohistochemistry using WFA in P-nase (a–c) ChABC (a′–c′) injected Tg P301S mice at 2 weeks post-injection. It showed the extent of depletion of PNNs by ChABC treatment, indicated by the dotted line. B. Profiles of WFA-positive PNNs in the PRh of P301S mice at higher magnification following P-nase or ChABC injection. Scale bar, 50 μm C. Stereological analysis of WFA-positive neurons in the PRh of P301S mice following P-nase or ChABC injection. Data are presented as mean ± SEM. A significant decrease in WFA staining is caused by ChABC injection in Tg P301S mice (P-nase n = 6, ChABC n = 6, t-test, **p < 0.01).CC BY · PubMed Central
Fig. 4 OR memory recovery after ChABC treatment in Tg P301S mice and AAV-P301S injected mice. A. Experimental protocol for the OR test after P-nase or ChABC injection. B. Three month-old homozygous P301S and age-matched control mice were injected with P-nase or ChABC. ChABC injected P301S mice showed a significant improvement in the OR memory compared to P-nase injected mice in spontaneous OR paradigm with a 3 h delay (P-nase n = 16, ChABC n = 13, t-test, ***p < 0.001) whereas control mice were not affected by ChABC (P-nase n = 7, ChABC n = 5) C. Seven month-old P301S Het and the age-matched littermate control mice were injected either with P-nase or ChABC. Spontaneous OR test with a 3 h delay was applied for testing OR memory after treatment. Similar pattern to that shown in B was observed. Although due to the variability in P301S Het mice, particularly those treated with P-nase, the results did not reach significance. Control: P-nase n = 4, ChABC n = 3; P301S: P-nase n = 4, ChABC n = 4 D. Mice from all AAV injected groups were tested by the spontaneous OR task with a 3 h delay-paradigm following P-nase or ChABC treatment to the PRh cortex. The OR deficit exhibited in the AAV-P301S injected mice (ANOVA with Tukey post-hoc, *p < 0.05) was significantly improved by ChABC treatment (t-test, *p < 0.05). AAV-fpmax: P-nase n = 6, ChABC n = 6; AAV-TauWT: P-nase n = 6, ChABC n = 6; AAV-P301S: P-nase n = 6, ChABC n = 6.
Fig. 4 OR memory recovery after ChABC treatment in Tg P301S mice and AAV-P301S injected mice. A. Experimental protocol for the OR test after P-nase or ChABC injection. B. Three month-old homozygous P301S and age-matched control mice were injected with P-nase or ChABC. ChABC injected P301S mice showed a significant improvement in the OR memory compared to P-nase injected mice in spontaneous OR paradigm with a 3 h delay (P-nase n = 16, ChABC n = 13, t-test, ***p < 0.001) whereas control mice were not affected by ChABC (P-nase n = 7, ChABC n = 5) C. Seven month-old P301S Het and the age-matched littermate control mice were injected either with P-nase or ChABC. Spontaneous OR test with a 3 h delay was applied for testing OR memory after treatment. Similar pattern to that shown in B was observed. Although due to the variability in P301S Het mice, particularly those treated with P-nase, the results did not reach significance. Control: P-nase n = 4, ChABC n = 3; P301S: P-nase n = 4, ChABC n = 4 D. Mice from all AAV injected groups were tested by the spontaneous OR task with a 3 h delay-paradigm following P-nase or ChABC treatment to the PRh cortex. The OR deficit exhibited in the AAV-P301S injected mice (ANOVA with Tukey post-hoc, *p < 0.05) was significantly improved by ChABC treatment (t-test, *p < 0.05). AAV-fpmax: P-nase n = 6, ChABC n = 6; AAV-TauWT: P-nase n = 6, ChABC n = 6; AAV-P301S: P-nase n = 6, ChABC n = 6.CC BY · PubMed Central
Fig. 5 OR memory deficit returns 5 weeks after ChABC treatment in Tg P301S mice PNNs were visualized by WFA staining in P-nase (A) or ChABC (B) injected mice 5 weeks post-injection. The PNNs present in the PRh of P-nase (a) or ChABC (b) injected mice were shown at higher magnification. C. Stereological quantification of WFA-positive cells in the PRh of P301S mice following P-nase (n = 5) or ChABC (n = 5) injection. There was no significant difference between groups (t-test, n.s: not significant, p = 0.072). D. ChABC and P-nase treated P301S mice showed similar level of deficit 5 weeks following ChABC injection. At this time point, ChABC treatment was no longer effective in restoring the OR memory in Tg P301S mice (P-nase n = 7, ChABC n = 6, t-test, n.s, p = 0.91). E. The exploration time for sample phase of control and P301S mice at 5 weeks after ChABC injection, indicating that each group presented comparable extent of motivation and that lack of motivation was not interfering with the results. Control; P-nase n = 6, ChABC n = 5, P301S; P-nase n = 7, ChABC n = 6.
Fig. 5 OR memory deficit returns 5 weeks after ChABC treatment in Tg P301S mice PNNs were visualized by WFA staining in P-nase (A) or ChABC (B) injected mice 5 weeks post-injection. The PNNs present in the PRh of P-nase (a) or ChABC (b) injected mice were shown at higher magnification. C. Stereological quantification of WFA-positive cells in the PRh of P301S mice following P-nase (n = 5) or ChABC (n = 5) injection. There was no significant difference between groups (t-test, n.s: not significant, p = 0.072). D. ChABC and P-nase treated P301S mice showed similar level of deficit 5 weeks following ChABC injection. At this time point, ChABC treatment was no longer effective in restoring the OR memory in Tg P301S mice (P-nase n = 7, ChABC n = 6, t-test, n.s, p = 0.91). E. The exploration time for sample phase of control and P301S mice at 5 weeks after ChABC injection, indicating that each group presented comparable extent of motivation and that lack of motivation was not interfering with the results. Control; P-nase n = 6, ChABC n = 5, P301S; P-nase n = 7, ChABC n = 6.CC BY · PubMed Central
Fig. 6 ChABC treatment altered synaptic transmission in the PRh of Tg P301S mice. A. Layer II/III fEPSP amplitudes after stimulation of temporal layer II/III input with different stimulus intensities. WT P-nase n = 11, P301S P-nase n = 11, P301S ChABC n = 11. Two-way RM ANOVA: there is a statistically significant interaction between group and intensity. Data are presented as mean ± SEM. ***p < 0.001 B. LTD induced by low-frequency stimulation is not different between P-nase injected WT control and P301S mice. Moreover, ChABC treatment to the PRh did not alter LTD in P301S mice. WT P-nase n = 7, P301S P-nase n = 7, P301S ChABC n = 6.
Fig. 6 ChABC treatment altered synaptic transmission in the PRh of Tg P301S mice. A. Layer II/III fEPSP amplitudes after stimulation of temporal layer II/III input with different stimulus intensities. WT P-nase n = 11, P301S P-nase n = 11, P301S ChABC n = 11. Two-way RM ANOVA: there is a statistically significant interaction between group and intensity. Data are presented as mean ± SEM. ***p < 0.001 B. LTD induced by low-frequency stimulation is not different between P-nase injected WT control and P301S mice. Moreover, ChABC treatment to the PRh did not alter LTD in P301S mice. WT P-nase n = 7, P301S P-nase n = 7, P301S ChABC n = 6.CC BY · PubMed Central
Fig. 7 Tauopathy after ChABC treatment in Tg P301S mice. Hyperphosphorylated tau was visualized by AT8 antibody immunostaining in the PRh of P-nase (A) and ChABC (B) injected mice at 2 weeks post-injection. AT8 (C) or NeuN-positive cells (D) were stereologically quantified in the PRh cortex of P301S mice (P-nase n = 5, ChABC n = 5). No significant influence of ChABC treatment on AT8 staining or neuronal cell number was present in the Tg P301S mice. E. The level of total tau protein and sarkosyl-insoluble tau in the PRh treated with either P-nase or ChABC was analyzed by Western blotting using anti-human tau antibody. No difference was present between the two groups. Western blotting with AT8 antibody showed the similar level of sarkosyl-insoluble hyperphosphorylated tau in the P301S mouse PRh treated with either P-nase or ChABC, indicating that the treatment did not affect insoluble tau pathology. Control; P-nase n = 2, ChABC n = 2, P301S; P-nase n = 4, ChABC n = 4.
Fig. 7 Tauopathy after ChABC treatment in Tg P301S mice. Hyperphosphorylated tau was visualized by AT8 antibody immunostaining in the PRh of P-nase (A) and ChABC (B) injected mice at 2 weeks post-injection. AT8 (C) or NeuN-positive cells (D) were stereologically quantified in the PRh cortex of P301S mice (P-nase n = 5, ChABC n = 5). No significant influence of ChABC treatment on AT8 staining or neuronal cell number was present in the Tg P301S mice. E. The level of total tau protein and sarkosyl-insoluble tau in the PRh treated with either P-nase or ChABC was analyzed by Western blotting using anti-human tau antibody. No difference was present between the two groups. Western blotting with AT8 antibody showed the similar level of sarkosyl-insoluble hyperphosphorylated tau in the P301S mouse PRh treated with either P-nase or ChABC, indicating that the treatment did not affect insoluble tau pathology. Control; P-nase n = 2, ChABC n = 2, P301S; P-nase n = 4, ChABC n = 4.CC BY · PubMed Central

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Authors
Yang, S., Cacquevel, M., Saksida, L. M., Bussey, T. J., Schneider, B. L., Aebischer, P., Melani, R., Pizzorusso, T., Fawcett, J. W., & Spillantini, M. G.
Affiliations
  • University of Cambridge (GB)
  • École Polytechnique Fédérale de Lausanne (CH)
  • Neuroscience Institute (IT)
Corresponding author
Spillantini, Maria Grazia
ORCID
Venue
Experimental Neurology
Publisher
Elsevier BV
Published
2015-03
Volume
265
Pages
48-58
ISSN
0014-4886 (ISSN-L)
DOI
10.1016/j.expneurol.2014.11.013
PMC
PMC4353684
OpenAlex
W2156939977
Cited by
138
References
54
Citations by year
2026: 12 · 2025: 11 · 2024: 15 · 2023: 9 · 2022: 13 · 2021: 13 · 2020: 13 · 2019: 15 · 2018: 12 · 2017: 10 · 2016: 9 · 2015: 6
FWCI
5.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Florence Research (University of Florence) (submittedVersion, other-oa)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • Scholarship@Western (Western University) (submittedVersion)
  • Scuola Normale Superiore di Pisa (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
Funders
  • Wellcome Trust
  • Christopher and Dana Reeve Foundation
  • Medical Research Council
  • National Institute for Health Research
  • Alzheimer’s Research UK
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
perineuronal nets, chondroitinase ABC, tauopathy, Alzheimer's disease, P301S tau, object recognition memory, perirhinal cortex, synaptic plasticity, synaptic transmission, neurodegeneration, memory recovery, tau hyperphosphorylation
MeSH terms
Animals, Cerebral Cortex, Humans, Injections, Intraventricular, Male, Memory, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Neuronal Plasticity, Organ Culture Techniques, Chondroitin ABC Lyase, Tauopathies, Mice

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