PMID- 25954034
OWN - NLM
STAT- MEDLINE
DCOM- 20160428
LR  - 20220129
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 24
IP  - 14
DP  - 2015 Jul 15
TI  - The pro-domains of neurotrophins, including BDNF, are linked to Alzheimer's 
      disease through a toxic synergy with Abeta.
PG  - 3929-38
LID - 10.1093/hmg/ddv130 [doi]
AB  - Brain-derived neurotrophic factor (BDNF) has a crucial role in learning and 
      memory by promoting neuronal survival and modulating synaptic connectivity. BDNF 
      levels are lower in the brains of individuals with Alzheimer's disease (AD), 
      suggesting a pathogenic involvement. The Drosophila orthologue of BDNF is the 
      highly conserved Neurotrophin 1 (DNT1). BDNF and DNT1 have the same overall 
      protein structure and can be cleaved, resulting in the conversion of a 
      full-length polypeptide into separate pro- and mature-domains. While the BDNF 
      mature-domain is neuroprotective, the role of the pro-domain is less clear. In 
      flies and mammalian cells, we have identified a synergistic toxic interaction 
      between the amyloid-beta peptide (Abeta1-42) and the pro-domains of both DNT1 and BDNF. 
      Specifically, we show that DNT1 pro-domain acquires a neurotoxic activity in the 
      presence of Abeta1-42. In contrast, DNT1 mature-domain is protective against Abeta1-42 
      toxicity. Likewise, in SH-SY5Y cell culture, BDNF pro-domain is toxic only in the 
      presence of Abeta1-42. Western blots indicate that this synergistic interaction 
      likely results from the Abeta1-42-induced upregulation of the BDNF pro-domain 
      receptor p75(NTR). The clinical relevance of these findings is underlined by a 
      greater than thirty fold increase in the ratio of BDNF pro- to mature-domains in 
      the brains of individuals with AD. This unbalanced BDNF pro:mature-domain ratio 
      in patients represents a possible biomarker of AD and may offer a target for 
      therapeutic intervention.
CI  - (c) The Author 2015. Published by Oxford University Press.
FAU - Lim, Jung Yeon
AU  - Lim JY
AD  - Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 
      3EH, UK.
FAU - Reighard, Charles P
AU  - Reighard CP
AD  - Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge 
      CB2 1GA, UK and.
FAU - Crowther, Damian C
AU  - Crowther DC
AD  - Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 
      3EH, UK, MedImmune Limited, Aaron Klug Building, Granta Park, Cambridge CB21 6GH, 
      UK dcc26@cam.ac.uk.
LA  - eng
GR  - G0700990/MRC_/Medical Research Council/United Kingdom
GR  - 082604/2/07/Z/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150507
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Genetic Markers)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-42))
RN  - 0 (neurotrophin 1, Drosophila)
RN  - 7171WSG8A2 (BDNF protein, human)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Alzheimer Disease/*genetics
MH  - Amyloid beta-Peptides/genetics/*metabolism
MH  - Animals
MH  - Brain/metabolism
MH  - Brain-Derived Neurotrophic Factor/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Drosophila/*genetics
MH  - Drosophila Proteins/genetics/*metabolism
MH  - Female
MH  - Genetic Markers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Nerve Growth Factors/genetics/*metabolism
MH  - Peptide Fragments/genetics/*metabolism
MH  - Protein Interaction Maps
MH  - Receptor, trkB/genetics/metabolism
MH  - Up-Regulation
PMC - PMC4476443
EDAT- 2015/05/09 06:00
MHDA- 2016/04/29 06:00
PMCR- 2015/05/07
CRDT- 2015/05/09 06:00
PHST- 2015/01/20 00:00 [received]
PHST- 2015/04/08 00:00 [accepted]
PHST- 2015/05/09 06:00 [entrez]
PHST- 2015/05/09 06:00 [pubmed]
PHST- 2016/04/29 06:00 [medline]
PHST- 2015/05/07 00:00 [pmc-release]
AID - ddv130 [pii]
AID - 10.1093/hmg/ddv130 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2015 Jul 15;24(14):3929-38. doi: 10.1093/hmg/ddv130. Epub 2015 May 
      7.