PMID- 22305478
OWN - NLM
STAT- MEDLINE
DCOM- 20130328
LR  - 20120903
IS  - 1558-1497 (Electronic)
IS  - 0197-4580 (Linking)
VI  - 33
IP  - 11
DP  - 2012 Nov
TI  - Dispersible amyloid beta-protein oligomers, protofibrils, and fibrils represent 
      diffusible but not soluble aggregates: their role in neurodegeneration in amyloid 
      precursor protein (APP) transgenic mice.
PG  - 2641-60
LID - 10.1016/j.neurobiolaging.2011.12.032 [doi]
AB  - Soluble amyloid beta-protein (Abeta) aggregates have been identified in the Alzheimer's 
      disease (AD) brain. Dispersed Abeta aggregates in the brain parenchyma are different 
      from soluble, membrane-associated and plaque-associated solid aggregates. They 
      are in mixture with the extra- or intracellular fluid but can be separated from 
      soluble proteins by ultracentrifugation. To clarify the role of dispersible Abeta 
      aggregates for neurodegeneration we analyzed 2 different amyloid precursor 
      protein (APP)-transgenic mouse models. APP23 mice overexpress human mutant APP 
      with the Swedish mutation. APP51/16 mice express high levels of human wild type 
      APP. Both mice develop Abeta-plaques. Dendritic degeneration, neuron loss, and loss 
      of asymmetric synapses were seen in APP23 but not in APP51/16 mice. The soluble 
      and dispersible fractions not separated from one another were received as 
      supernatant after centrifugation of native forebrain homogenates at 14,000 x g. 
      Subsequent ultracentrifugation separated the soluble, i.e., the supernatant, from 
      the dispersible fraction, i.e., the resuspended pellet. The major biochemical 
      difference between APP23 and APP51/16 mice was that APP23 mice exhibited higher 
      levels of dispersible Abeta oligomers, protofibrils and fibrils precipitated with 
      oligomer (A11) and protofibril/fibril (B10AP) specific antibodies than APP51/16 
      mice. These differences, rather than soluble Abeta and Abeta plaque pathology were 
      associated with dendritic degeneration, neuron, and synapse loss in APP23 mice in 
      comparison with APP51/16 mice. Immunoprecipitation of dispersible Abeta oligomers, 
      protofibrils, and fibrils revealed that they were associated with APP C-terminal 
      fragments (APP-CTFs). These results indicate that dispersible Abeta oligomers, 
      protofibrils, and fibrils represent an important pool of Abeta aggregates in the 
      brain that critically interact with membrane-associated APP C-terminal fragments. 
      The concentration of dispersible Abeta aggregates, thereby, presumably determines 
      its toxicity.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Rijal Upadhaya, Ajeet
AU  - Rijal Upadhaya A
AD  - Laboratory of Neuropathology, Institute of Pathology, Center for Clinical 
      Research at the University of Ulm, Ulm, Germany.
FAU - Capetillo-Zarate, Estibaliz
AU  - Capetillo-Zarate E
FAU - Kosterin, Irina
AU  - Kosterin I
FAU - Abramowski, Dorothee
AU  - Abramowski D
FAU - Kumar, Sathish
AU  - Kumar S
FAU - Yamaguchi, Haruyasu
AU  - Yamaguchi H
FAU - Walter, Jochen
AU  - Walter J
FAU - Fandrich, Marcus
AU  - Fandrich M
FAU - Staufenbiel, Matthias
AU  - Staufenbiel M
FAU - Thal, Dietmar Rudolf
AU  - Thal DR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120202
PL  - United States
TA  - Neurobiol Aging
JT  - Neurobiology of aging
JID - 8100437
RN  - 0 (Amyloid beta-Protein Precursor)
SB  - IM
MH  - Alzheimer Disease/genetics/*metabolism/pathology
MH  - Amyloid beta-Protein Precursor/genetics/*metabolism
MH  - Animals
MH  - Brain/metabolism/pathology
MH  - Disease Models, Animal
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mutation/genetics
MH  - Neurons/*metabolism/pathology
MH  - Plaque, Amyloid/*metabolism/pathology
MH  - *Protein Multimerization
MH  - Synapses/metabolism/*pathology
EDAT- 2012/02/07 06:00
MHDA- 2013/03/30 06:00
CRDT- 2012/02/07 06:00
PHST- 2011/11/08 00:00 [received]
PHST- 2011/12/27 00:00 [revised]
PHST- 2011/12/28 00:00 [accepted]
PHST- 2012/02/07 06:00 [entrez]
PHST- 2012/02/07 06:00 [pubmed]
PHST- 2013/03/30 06:00 [medline]
AID - S0197-4580(11)00577-X [pii]
AID - 10.1016/j.neurobiolaging.2011.12.032 [doi]
PST - ppublish
SO  - Neurobiol Aging. 2012 Nov;33(11):2641-60. doi: 
      10.1016/j.neurobiolaging.2011.12.032. Epub 2012 Feb 2.