1. Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology.
- Author
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Yang S, Cacquevel M, Saksida LM, Bussey TJ, Schneider BL, Aebischer P, Melani R, Pizzorusso T, Fawcett JW, and Spillantini MG
- Subjects
- Animals, Cerebral Cortex drug effects, Cerebral Cortex pathology, Humans, Injections, Intraventricular, Male, Memory drug effects, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net drug effects, Nerve Net pathology, Neuronal Plasticity drug effects, Organ Culture Techniques, Tauopathies drug therapy, Tauopathies pathology, Cerebral Cortex enzymology, Chondroitin ABC Lyase administration & dosage, Memory physiology, Nerve Net enzymology, Neuronal Plasticity physiology, Tauopathies enzymology
- 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., (Copyright © 2015. Published by Elsevier Inc.)
- Published
- 2015
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