Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology
Open accessAbstract
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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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)”
From Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration (2024) · cites this paper as Yang et al. 2015
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 measuredThe Yang et al. investigation was limited to both brain region (perirhinal cortex) and age (3 months).
“this investigation was limited to both brain region (perirhinal cortex) and age (3 months).”
From Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration (2024) · cites this paper as Yang et al. 2015
The Results section, “ChABC injection restores memory in Tg P301S mice” (page unavailable), describes injections focused on the perirhinal cortex, supporting the regional part of the claim. But the study included both 3-month-old mice and 7-month-old heterozygous mice, so it was not limited to age 3 months. The authors also observed some spread of enzyme activity into adjacent regions. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTreating tauopathy mice with Ch-ABC to the PrC restored object memory to normal levels.
“Treating these animals with Ch--ABC to the PrC restored object memory to normal levels (Yang et al., 2015)”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Yang et al., 2015
There is inconsistency in PNN findings in transgenic mouse models of Alzheimer's disease.
“There is some inconsistency on PNN findings in the transgenic mouse model of AD.”
From Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis (2020) · cites this paper as Yang et al., 2015
The Introduction describes a P301S tau transgenic mouse model, and the Results discuss PNN manipulation, but neither compares PNN findings across Alzheimer's disease mouse models. Searches for inconsistent, conflicting, increased, and decreased PNN findings found no passage addressing the claimed inconsistency. (LLM, conf=0.72)
Experimental — accuracy not yet measuredChABC injections into perirhinal cortices from transgenic mice with tau pathology restored object recognition memory.
“Remarkably, ChABC injections into perirhinal cortices from transgenic mice with tau pathology restored even the object recognition memory of these animals (Yang et al., 2015).”
From Damaged Neocortical Perineuronal Nets Due to Experimental Focal Cerebral Ischemia in Mice, Rats and Sheep (2017) · cites this paper as Yang et al., 2015
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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)
- 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
- hybrid
- doi.org
- 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
- Health Sciences › Medicine › Physiology › 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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