PMID- 21504138
OWN - NLM
STAT- MEDLINE
DCOM- 20120131
LR  - 20191112
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 21
IP  - 4
DP  - 2010
TI  - Cognitive deficits associated with alteration of synaptic metaplasticity precede 
      plaque deposition in AbetaPP23 transgenic mice.
PG  - 1367-81
AB  - Synaptic dysfunction is an early event in the development of Alzheimer's disease 
      (AD) and relates closely to the cognitive impairment characterizing this 
      neurodegenerative process. A causative association has been proposed, largely on 
      the basis of in vitro studies, between memory decline, soluble amyloid-beta (Abeta) 
      oligomers and alterations of glutamatergic neurotransmission. We aimed here to 
      characterize in vivo N-methyl-D-aspartate receptor (NMDAR)-mediated signaling, at 
      an early stage of AD, before extracellular amyloid plaques are deposited. We 
      assessed the functional link between cognitive abilities and NMDAR-mediated 
      pharmacological responses of six-month-old AbetaPP23 transgenic mice (AbetaPP23tg), 
      overexpressing the human amyloid-beta protein precursor carrying the Swedish double 
      mutation. We found evidence of cognitive impairments in these mice, indicated by 
      deficits in the delayed-non-matching-to-place task. Alterations of NMDAR-mediated 
      signaling in this mouse model were confirmed by the reduced sensitivity of 
      motor-activation and working memory to pharmacological inhibition of NMDAR 
      activity. At the molecular level, AbetaPP23tg mice show hippocampal alterations in 
      the trafficking of synaptic NMDAR subunits NR2A and NR2B and at an 
      ultrastructural analysis show Abeta oligomers intracellularly localized in the 
      synaptic compartments. Importantly, the behavioral and biochemical alterations of 
      NMDAR signaling are associated with the inhibition of long-term synaptic 
      potentiation and inversion of metaplasticity at CA1 synapses in hippocampal 
      slices from AbetaPP23tg mice. These results indicate a general impairment of 
      synaptic function and learning and memory in young AbetaPP23tg mice with Abeta 
      oligomers but no amyloid plaques.
FAU - Balducci, Claudia
AU  - Balducci C
AD  - Department of Neuroscience, Department of Cardiovascular Research, Mario Negri 
      Institute for Pharmacological Research, Milan, Italy.
FAU - Tonini, Raffaella
AU  - Tonini R
FAU - Zianni, Elisa
AU  - Zianni E
FAU - Nazzaro, Cristiano
AU  - Nazzaro C
FAU - Fiordaliso, Fabio
AU  - Fiordaliso F
FAU - Salio, Monica
AU  - Salio M
FAU - Vismara, Lorenzo
AU  - Vismara L
FAU - Gardoni, Fabrizio
AU  - Gardoni F
FAU - Di Luca, Monica
AU  - Di Luca M
FAU - Carli, Mirjana
AU  - Carli M
FAU - Forloni, Gianluigi
AU  - Forloni G
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Peptide Fragments)
SB  - IM
MH  - Amyloid beta-Peptides/*genetics
MH  - Amyloid beta-Protein Precursor/*genetics
MH  - Animals
MH  - Behavior, Animal/physiology
MH  - Cognition Disorders/*genetics/physiopathology
MH  - Male
MH  - Maze Learning/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - *Neuronal Plasticity/genetics
MH  - Peptide Fragments/*genetics
MH  - Plaque, Amyloid/*genetics/pathology
MH  - Synapses/*genetics/pathology
EDAT- 2010/01/01 00:00
MHDA- 2012/02/01 06:00
CRDT- 2011/04/20 06:00
PHST- 2011/04/20 06:00 [entrez]
PHST- 2010/01/01 00:00 [pubmed]
PHST- 2012/02/01 06:00 [medline]
AID - 10.3233/jad-2010-100675 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2010;21(4):1367-81. doi: 10.3233/jad-2010-100675.