NR AWJM
AU Mallucci,G.R.; White,M.D.; Dickinson,A.; Brandner,S.; Khatun,H.; Powell,A.D.; Jefferys,J.G.R.; Collinge,J.
TI Targeting cellular prion protein reverses early cognitive deficits in prion-infected mice
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-30
PT Konferenz-Vortrag
AB
Currently no treatment can prevent the progressive cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that depleting endogenous neuronal prion protein (PrPc) in prion-infected mice halted progression to clinical symptoms and prevented neuronal loss, as well as reversing early spongiform degeneration (1). Therefore, we now asked whether the recovery of early pathology reflects a capacity for functional as well as morphological recovery. We asked whether early pathology is associated with neurophysiological, cognitive and behavioural deficits and whether these could recover in parallel with reversal of spongiform degeneration. We therefore examined hippocampal function, testing novel object recognition memory and species-specific behaviours in vivo, and measured synaptic function ex-vivo over several weeks in prion infected animals. We used transgenic mice in which reversal of early spongiform pathology in prion infection occurs due to Cre-recombinase mediated PrP depletion in neurons at ~8 weeks post infection as well as control mice that do not undergo PrP depletion (2). We found that prion-infected mice of both genotpes developed early cognitive and behavioural impairments associated with impaired hippocampal synaptic function, long before the occurrence of motor symptoms and neuronal loss, and also before synapse loss was apparent. Remarkably, when neuronal PrPc was depleted, learning and behavioural deficits reversed and synaptic function recovered, in parallel with reversal of early pathological change. Further, these occurred before extensive PrPsc deposits accumulated and recovered rapidly after PrPc depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrPsc. Our combined neurophysiological and behavioural analyses provide the first direct evidence for early synaptic failure in prion disease producing functional impairment, before neurodegeneration is established. These data suggest that early therapeutic intervention in human prion disease might also lead to recovery of cognitive and behavioural symptoms.
(1) Mallucci, G. et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871-874 (2003) (2) Mallucci, G. R. et al. Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 21, 202-210 (2002)
AD G.R. Mallucci (g.mallucci@prion.ucl.ac.uk), M.D. White, A. Dickinson, S. Brandner, J. Collinge: MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK; H.Khatun, A.D. Powell, J.G.R. Jefferys: 2Department of Neurophysiology, Division of Neuroscience, University of Birmingham, Birmingham, B15 2TT, UK
SP englisch
PO Italien