title: Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology.
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.
authors.affiliation: John Van Geest Centre for Brain Repair, University of Cambridge, Robinson Way, Cambridge CB2 0PY, United Kingdom.
authors.forename: Sujeong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Cacquevel
authors.affiliation: Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, United Kingdom; MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, United Kingdom.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Saksida
authors.affiliation: Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, United Kingdom; MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, United Kingdom.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bussey
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.affiliation: Inst Neuroscience CNR, via Moruzzi 1, 56125 Pisa, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Melani
authors.affiliation: Inst Neuroscience CNR, via Moruzzi 1, 56125 Pisa, Italy; NEUROFARBA Dept, University of Florence, Area S. Salvi Pad. 26, 50135 Florence, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
authors.affiliation: John Van Geest Centre for Brain Repair, University of Cambridge, Robinson Way, Cambridge CB2 0PY, United Kingdom.
authors.forename: James W
authors.initials: JW
authors.lastname: Fawcett
authors.affiliation: John Van Geest Centre for Brain Repair, University of Cambridge, Robinson Way, Cambridge CB2 0PY, United Kingdom. Electronic address: mgs11@cam.ac.uk.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019765:Chondroitin ABC Lyase / Q000008:administration & dosage*; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D024801:Tauopathies / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
chemical_list: D019765:Chondroitin ABC Lyase
keywords: Chondroitinase ABC; Memory dementia perineuronal net; Microtubule-associated protein; Object recognition TEST; Tauopathy