Perineuronal net digestionwith chondroitinase restores memory inmice with tau pathology
Schneider, Bernard L
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Yang, S., Cacquevel, M., Saksida, L., Bussey, T., Schneider, B. L., Aebischer, P., Melani, R., et al. (2014). Perineuronal net digestionwith chondroitinase restores memory inmice with tau pathology. Experimental Neurology, 265 48-58. https://doi.org/10.1016/j.expneurol.2014.11.013
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 3 month-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 1 week 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, Microtubule-associated protein, Tauopathy, Memory dementia perineuronal net, Object recognition TEST
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.
Medical Research Council (G1000864)
Medical Research Council (G0001354)
External DOI: https://doi.org/10.1016/j.expneurol.2014.11.013
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246828
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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