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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 


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.



Chondroitinase ABC, Memory dementia perineuronal net, Microtubule-associated protein, Object recognition TEST, Tauopathy, Animals, Cerebral Cortex, Chondroitin ABC Lyase, Humans, Injections, Intraventricular, Male, Memory, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Neuronal Plasticity, Organ Culture Techniques, Tauopathies

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Exp Neurol

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Elsevier BV
Medical Research Council (G1000864)
Medical Research Council (G0001354)
MRC (G1000864)
Wellcome Trust (089703/Z/09/Z)
This work was supported by the European Union Framework 7 Project Plasticise (S.Y., M.C., M.G.S., J.W.F., P.R., P.A., B.L.S.), the Wellcome Trust (L.M.S., T.J.B.), the Alzheimer's Research UK (M.G.S.), and the UK Medical Research Council (L.M.S., T.J.B.). J.W.F.'s work is supported by the ERC-ECMneuro, the Christopher and Dana Reeve Foundation and the NIHR Cambridge biomedical research center.