PMID- 22426239
OWN - NLM
STAT- MEDLINE
DCOM- 20120921
LR  - 20120521
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 210
DP  - 2012 May 17
TI  - Amyloid beta selectively modulates neuronal TrkB alternative transcript 
      expression with implications for Alzheimer's disease.
PG  - 363-74
LID - 10.1016/j.neuroscience.2012.02.037 [doi]
AB  - Dysregulation in brain-derived neurotrophic factor (BDNF)/full-length TrkB 
      (TrkB-TK+) signaling is implicated in promoting neurodegeneration in Alzheimer's 
      disease (AD). BDNF/TrkB-TK+ signaling can be modulated by the presence of 
      truncated TrkB isoforms (TrkB-TK-, TrkB-Shc). All TrkB isoforms are encoded by 
      different alternative transcripts. In this study, we assessed if expression of 
      the three main TrkB alternative transcripts, TrkB-TK+, TrkB-TK-, and TrkB-Shc are 
      altered in AD. Using a cohort of control and AD brains (n=29), we surveyed the 
      hippocampus, temporal cortex, occipital cortex, and cerebellum and found specific 
      increases in TrkB-Shc, a neuron-specific transcript, in the AD hippocampus. No 
      significant changes were detected in TrkB-TK+ and TrkB-TK- transcript levels in 
      AD in any brain region examined. Corresponding changes in truncated TrkB protein 
      levels were found in the hippocampus, although a significant increase in the 
      temporal cortex was also observed. Our findings suggested that neuron-specific 
      changes in TrkB may be occurring in AD; thus, we determined whether TrkB-Shc 
      expression could be modulated by amyloid beta 1-42 (Abeta(42)). We found increased 
      TrkB-Shc mRNA levels in differentiated SHSY5Y neuronal cell-lines exposed to 
      fibril-containing Abeta(42) preparations. When we assessed the cellular impact of 
      increased TrkB-Shc, we found co-localization between TrkB-Shc and TrkB-TK+. 
      Interestingly, TrkB-Shc overexpression selectively attenuated 
      BDNF/TrkB-TK+-mediated signaling via the mitogen-activated protein kinase kinase 
      (MEK) pathway, but not the protein kinase B pathway. In AD, MEK signaling is 
      increased in vulnerable neurons and linked to abnormal phosphorylation of 
      cytoskeletal proteins. Altogether, our findings suggest that elevated TrkB-Shc 
      expression in AD may function as a compensatory response in neurons in AD to 
      promote survival.
CI  - Crown Copyright (c) 2012. Published by Elsevier Ltd. All rights reserved.
FAU - Wong, J
AU  - Wong J
AD  - Illawarra Health and Medical Research Institute, University of Wollongong, 
      Northfields Avenue, Wollongong, NSW 2522, Australia. jwong@uow.edu.au
FAU - Higgins, M
AU  - Higgins M
FAU - Halliday, G
AU  - Halliday G
FAU - Garner, B
AU  - Garner B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120228
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Protein Isoforms)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Alternative Splicing
MH  - Alzheimer Disease/*metabolism
MH  - Amyloid beta-Peptides/*metabolism
MH  - Brain/*metabolism
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Line
MH  - Female
MH  - Gene Expression Profiling
MH  - Humans
MH  - Male
MH  - Microscopy, Atomic Force
MH  - Middle Aged
MH  - Neurons/*metabolism
MH  - Protein Isoforms
MH  - Receptor, trkB/genetics/*metabolism
MH  - Signal Transduction/physiology
MH  - *Transcription, Genetic
EDAT- 2012/03/20 06:00
MHDA- 2012/09/22 06:00
CRDT- 2012/03/20 06:00
PHST- 2011/11/20 00:00 [received]
PHST- 2012/02/19 00:00 [revised]
PHST- 2012/02/21 00:00 [accepted]
PHST- 2012/03/20 06:00 [entrez]
PHST- 2012/03/20 06:00 [pubmed]
PHST- 2012/09/22 06:00 [medline]
AID - S0306-4522(12)00180-7 [pii]
AID - 10.1016/j.neuroscience.2012.02.037 [doi]
PST - ppublish
SO  - Neuroscience. 2012 May 17;210:363-74. doi: 10.1016/j.neuroscience.2012.02.037. 
      Epub 2012 Feb 28.