PMID- 25942043
OWN - NLM
STAT- MEDLINE
DCOM- 20160107
LR  - 20181113
IS  - 2158-3188 (Electronic)
IS  - 2158-3188 (Linking)
VI  - 5
IP  - 5
DP  - 2015 May 5
TI  - TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and 
      memory deficits without affecting beta-amyloidosis in 5XFAD mice.
PG  - e562
LID - 10.1038/tp.2015.55 [doi]
AB  - Accumulating evidence shows that brain-derived neurotrophic factor (BDNF) and its 
      receptor tropomyosin-related kinase B (TrkB) significantly decrease early in 
      Alzheimer's disease (AD). However, it remains unclear whether BDNF/TrkB 
      reductions may be mechanistically involved in the pathogenesis of AD. To address 
      this question, we generated 5XFAD transgenic mice with heterozygous TrkB knockout 
      (TrkB(+/-).5XFAD), and tested the effects of TrkB reduction on AD-like features 
      in this mouse model during an incipient stage that shows only modest amyloid-beta 
      (Abeta) pathology and retains normal mnemonic function. TrkB(+/-) reduction 
      exacerbated memory declines in 5XFAD mice at 4-5 months of age as assessed by the 
      hippocampus-dependent spontaneous alternation Y-maze task, while the memory 
      performance was not affected in TrkB(+/-) mice. Meanwhile, TrkB(+/-).5XFAD mice 
      were normal in nest building, a widely used measure for social behavior, 
      suggesting the memory-specific aggravation of AD-associated behavioral 
      impairments. We found no difference between TrkB(+/-).5XFAD and 5XFAD control 
      mice in cerebral plaque loads, Abeta concentrations including total Abeta42 and soluble 
      oligomers and beta-amyloidogenic processing of amyloid precursor protein. 
      Interestingly, reductions in hippocampal expression of AMPA/NMDA glutamate 
      receptor subunits as well as impaired signaling pathways downstream to TrkB such 
      as CREB (cAMP response element-binding protein) and Akt/GSK-3beta (glycogen synthase 
      kinase-3beta) were observed in TrkB(+/-).5XFAD mice but not in 5XFAD mice. Among 
      these signaling aberrations, only Akt/GSK-3beta dysfunction occurred in TrkB(+/-) 
      mice, while others were synergistic consequences between TrkB reduction and 
      subthreshold levels of Abeta in TrkB(+/-).5XFAD mice. Collectively, our results 
      indicate that reduced TrkB does not affect beta-amyloidosis but exacerbates the 
      manifestation of hippocampal mnemonic and signaling dysfunctions in early AD.
FAU - Devi, L
AU  - Devi L
AD  - Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA.
FAU - Ohno, M
AU  - Ohno M
AD  - 1] Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA [2] 
      Department of Psychiatry, New York University Langone Medical Center, New York, 
      NY, USA.
LA  - eng
GR  - R03 AG044703/AG/NIA NIH HHS/United States
GR  - AG044703/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150505
PL  - United States
TA  - Transl Psychiatry
JT  - Translational psychiatry
JID - 101562664
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (amyloid beta-protein (1-42))
RN  - EC 2.7.10.1 (Ntrk2 protein, mouse)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Alzheimer Disease/*genetics/metabolism/pathology
MH  - Amyloid beta-Peptides/*metabolism
MH  - Animals
MH  - Brain/*metabolism/pathology
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Disease Models, Animal
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Heterozygote
MH  - Membrane Glycoproteins/*genetics
MH  - Memory
MH  - Memory Disorders/*genetics/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Peptide Fragments/*metabolism
MH  - Plaque, Amyloid/*genetics/pathology
MH  - Protein-Tyrosine Kinases/*genetics
MH  - Proto-Oncogene Proteins c-akt
MH  - Receptors, AMPA/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Signal Transduction
PMC - PMC4471286
EDAT- 2015/05/06 06:00
MHDA- 2016/01/08 06:00
PMCR- 2015/05/01
CRDT- 2015/05/06 06:00
PHST- 2015/01/17 00:00 [received]
PHST- 2015/03/06 00:00 [revised]
PHST- 2015/03/24 00:00 [accepted]
PHST- 2015/05/06 06:00 [entrez]
PHST- 2015/05/06 06:00 [pubmed]
PHST- 2016/01/08 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - tp201555 [pii]
AID - 10.1038/tp.2015.55 [doi]
PST - epublish
SO  - Transl Psychiatry. 2015 May 5;5(5):e562. doi: 10.1038/tp.2015.55.