Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice.
Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrP(C)) (the precursor of its disease-associated isoform, PrP(Sc)) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrP(C) is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.
Mallucci
Giovanna R
GR
MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom. g.mallucci@prion.ucl.ac.uk
White
Melanie D
MD
Farmer
Michael
M
Dickinson
Andrew
A
Khatun
Husna
H
Powell
Andrew D
AD
Brandner
Sebastian
S
Jefferys
John G R
JG
Collinge
John
J
D000818:Animals; D001369:Axons / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000517:prevention & control* / Q000523:psychology*; D004192:Discrimination, Psychological / Q000502:physiology; D004594:Electrophysiology; D006624:Hippocampus / Q000473:pathology; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000523:psychology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology; D009425:Nesting Behavior / Q000502:physiology; D018621:PrPC Proteins / Q000235:genetics*; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology / Q000523:psychology*; D011597:Psychomotor Performance / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000473:pathology / Q000502:physiology; D014796:Visual Perception / Q000502:physiology
D018621:PrPC Proteins