PMID- 23211096
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121206
LR  - 20211021
IS  - 2047-9158 (Print)
IS  - 2047-9158 (Electronic)
IS  - 2047-9158 (Linking)
VI  - 1
IP  - 1
DP  - 2012 Mar 22
TI  - RNAi-mediated knock-down of Dab and Numb attenuate Abeta levels via gamma-secretase 
      mediated APP processing.
PG  - 8
LID - 10.1186/2047-9158-1-8 [doi]
AB  - Amyloid-beta-protein (Abeta), the key component of senile plaques in Alzheimer's 
      disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage 
      of beta-secretase and then gamma-secretase. APP adaptor proteins with 
      phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: 
      NUMB), can bind to and interact with the conserved YENPTY-motif in the APP 
      C-terminus. Here we describe, for the first time, the effects of RNAi knock-down 
      of Dab and Numb expression on APP processing and Abeta production. RNAi knock-down 
      of Dab and Numb in H4 human neuroglioma cells stably transfected to express 
      either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of 
      APP-C-terminal fragments (APP-CTFs) and lowered Abeta levels in both cell lines by 
      inhibiting gamma-secretase cleavage of APP. Finally, RNAi knock-down of APP also 
      reduced levels of Numb in H4-APP cells. These findings suggest that 
      pharmacologically blocking interaction of APP with Dab and Numb may provide novel 
      therapeutic strategies of AD. The notion of attenuating gamma-secretase cleavage of 
      APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with 
      regard to therapeutic potential, given that side effects of gamma-secretase 
      inhibition owing to impaired proteolysis of other gamma-secretase substrates, e.g. 
      Notch, might be avoided.
FAU - Xie, Zhongcong
AU  - Xie Z
AD  - Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute 
      for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical 
      School, Charlestown, MA 02129-2060, USA. zxie@partners.org.
FAU - Dong, Yuanlin
AU  - Dong Y
FAU - Maeda, Uta
AU  - Maeda U
FAU - Xia, Weiming
AU  - Xia W
FAU - Tanzi, Rudolph E
AU  - Tanzi RE
LA  - eng
GR  - R01 MH060009/MH/NIMH NIH HHS/United States
PT  - Journal Article
DEP - 20120322
PL  - England
TA  - Transl Neurodegener
JT  - Translational neurodegeneration
JID - 101591861
PMC - PMC3514095
EDAT- 2012/12/06 06:00
MHDA- 2012/12/06 06:01
PMCR- 2012/03/22
CRDT- 2012/12/06 06:00
PHST- 2011/12/25 00:00 [received]
PHST- 2012/03/22 00:00 [accepted]
PHST- 2012/12/06 06:00 [entrez]
PHST- 2012/12/06 06:00 [pubmed]
PHST- 2012/12/06 06:01 [medline]
PHST- 2012/03/22 00:00 [pmc-release]
AID - 2047-9158-1-8 [pii]
AID - 10.1186/2047-9158-1-8 [doi]
PST - epublish
SO  - Transl Neurodegener. 2012 Mar 22;1(1):8. doi: 10.1186/2047-9158-1-8.