PMID- 23844236
OWN - NLM
STAT- MEDLINE
DCOM- 20140207
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 7
DP  - 2013
TI  - The impact of Bdnf gene deficiency to the memory impairment and brain pathology 
      of APPswe/PS1dE9 mouse model of Alzheimer's disease.
PG  - e68722
LID - 10.1371/journal.pone.0068722 [doi]
LID - e68722
AB  - Brain-derived neurotrophic factor (BDNF) importantly regulates learning and 
      memory and supports the survival of injured neurons. Reduced BDNF levels have 
      been detected in the brains of Alzheimer's disease (AD) patients but the exact 
      role of BDNF in the pathophysiology of the disorder remains obscure. We have 
      recently shown that reduced signaling of BDNF receptor TrkB aggravates memory 
      impairment in APPswe/PS1dE9 (APdE9) mice, a model of AD. The present study 
      examined the influence of Bdnf gene deficiency (heterozygous knockout) on spatial 
      learning, spontaneous exploratory activity and motor coordination/balance in 
      middle-aged male and female APdE9 mice. We also studied brain BDNF protein levels 
      in APdE9 mice in different ages showing progressive amyloid pathology. Both APdE9 
      and Bdnf mutations impaired spatial learning in males and showed a similar trend 
      in females. Importantly, the effect was additive, so that double mutant mice 
      performed the worst. However, APdE9 and Bdnf mutations influenced spontaneous 
      locomotion in contrasting ways, such that locomotor hyperactivity observed in 
      APdE9 mice was normalized by Bdnf deficiency. Obesity associated with Bdnf 
      deficiency did not account for the reduced hyperactivity in double mutant mice. 
      Bdnf deficiency did not alter amyloid plaque formation in APdE9 mice. Before 
      plaque formation (3 months), BDNF protein levels where either reduced (female) or 
      unaltered (male) in the APdE9 mouse cortex. Unexpectedly, this was followed by an 
      age-dependent increase in mature BDNF protein. Bdnf mRNA and phospho-TrkB levels 
      remained unaltered in the cortical tissue samples of middle-aged APdE9 mice. 
      Immunohistological studies revealed increased BDNF immunoreactivity around 
      amyloid plaques indicating that the plaques may sequester BDNF protein and 
      prevent it from activating TrkB. If similar BDNF accumulation happens in human AD 
      brains, it would suggest that functional BDNF levels in the AD brains are even 
      lower than reported, which could partially contribute to learning and memory 
      problems of AD patients.
FAU - Rantamaki, Tomi
AU  - Rantamaki T
AD  - Neuroscience Center, University of Helsinki, Helsinki, Finland.
FAU - Kemppainen, Susanna
AU  - Kemppainen S
FAU - Autio, Henri
AU  - Autio H
FAU - Staven, Saara
AU  - Staven S
FAU - Koivisto, Hennariikka
AU  - Koivisto H
FAU - Kojima, Masami
AU  - Kojima M
FAU - Antila, Hanna
AU  - Antila H
FAU - Miettinen, Pasi O
AU  - Miettinen PO
FAU - Karkkainen, Elisa
AU  - Karkkainen E
FAU - Karpova, Nina
AU  - Karpova N
FAU - Vesa, Liisa
AU  - Vesa L
FAU - Lindemann, Lothar
AU  - Lindemann L
FAU - Hoener, Marius C
AU  - Hoener MC
FAU - Tanila, Heikki
AU  - Tanila H
FAU - Castren, Eero
AU  - Castren E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130703
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Presenilin-1)
SB  - IM
MH  - Alzheimer Disease/complications/*genetics/*pathology
MH  - Amyloid beta-Protein Precursor/genetics
MH  - Animals
MH  - Body Weight/genetics
MH  - Brain/metabolism/pathology
MH  - Brain-Derived Neurotrophic Factor/deficiency/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Environment
MH  - Female
MH  - Humans
MH  - Hyperkinesis/genetics
MH  - Male
MH  - Maze Learning
MH  - Memory
MH  - Memory Disorders/*etiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Plaque, Amyloid
MH  - Presenilin-1/genetics
MH  - Psychomotor Performance
PMC - PMC3700921
COIS- Competing Interests: Marius C. Hoener and Lothar Lindemann are employees of F. 
      Hoffmann-La Roche Ltd. Tomi Rantamaki, Hanna Antila and Eero Castren have 
      developed an analytical method that can be used to detect the levels or 
      modifications (e.g. phosphorylation) of cellular proteins (FIN/US Provisional 
      patent pending). This method can be used to screen for regulators of TrkB 
      receptor signaling. This method has not been used in the current study. All other 
      authors declare that they do not have any potential conflicts of interest related 
      to this study.
EDAT- 2013/07/12 06:00
MHDA- 2014/02/08 06:00
PMCR- 2013/07/03
CRDT- 2013/07/12 06:00
PHST- 2012/11/08 00:00 [received]
PHST- 2013/06/02 00:00 [accepted]
PHST- 2013/07/12 06:00 [entrez]
PHST- 2013/07/12 06:00 [pubmed]
PHST- 2014/02/08 06:00 [medline]
PHST- 2013/07/03 00:00 [pmc-release]
AID - PONE-D-12-34631 [pii]
AID - 10.1371/journal.pone.0068722 [doi]
PST - epublish
SO  - PLoS One. 2013 Jul 3;8(7):e68722. doi: 10.1371/journal.pone.0068722. Print 2013.