PMID- 23024787
OWN - NLM
STAT- MEDLINE
DCOM- 20130215
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 9
DP  - 2012
TI  - Dynamin 1 regulates amyloid generation through modulation of BACE-1.
PG  - e45033
LID - e45033
AB  - BACKGROUND: Several lines of investigation support the notion that endocytosis is 
      crucial for Alzheimer's disease (AD) pathogenesis. Substantial evidence have 
      already been reported regarding the mechanisms underlying amyloid precursor 
      protein (APP) traffic, but the regulation of beta-site APP-Cleaving Enzyme 1 
      (BACE-1) distribution among endosomes, TGN and plasma membrane remains unclear. 
      Dynamin, an important adaptor protein that controls sorting of many molecules, 
      has recently been associated with AD but its functions remain controversial. Here 
      we studied possible roles for dynamin 1 (dyn1) in Abeta biogenesis. PRINCIPAL 
      FINDINGS: We found that genetic perturbation of dyn1 reduces both secreted and 
      intracellular Abeta levels in cell culture. There is a dramatic reduction in BACE-1 
      cleavage products of APP (sAPPbeta and betaCTF). Moreover, dyn1 knockdown (KD) leads to 
      BACE-1 redistribution from the Golgi-TGN/endosome to the cell surface. There is 
      an increase in the amount of surface holoAPP upon dyn1 KD, with resultant 
      elevation of alpha-secretase cleavage products sAPPalpha and alphaCTF. But no changes are 
      seen in the amount of nicastrin (NCT) or PS1 N-terminal fragment (NTF) at cell 
      surface with dyn1 KD. Furthermore, treatment with a selective dynamin inhibitor 
      Dynasore leads to similar reduction in betaCTF and Abeta levels, comparable to changes 
      with BACE inhibitor treatment. But combined inhibition of BACE-1 and dyn1 does 
      not lead to further reduction in Abeta, suggesting that the Abeta-lowering effects of 
      dynamin inhibition are mainly mediated through regulation of BACE-1 
      internalization. Abeta levels in dyn1(-/-) primary neurons, as well as in 3-month 
      old dyn1 haploinsufficient animals with AD transgenic background are consistently 
      reduced when compared to their wildtype counterparts. CONCLUSIONS: In summary, 
      these data suggest a previously unknown mechanism by which dyn1 affects amyloid 
      generation through regulation of BACE-1 subcellular localization and therefore 
      its enzymatic activities.
FAU - Zhu, Li
AU  - Zhu L
AD  - Department of Neurology and Alzheimer's Disease Research Center, Mount Sinai 
      School of Medicine, New York, New York, United States of America.
FAU - Su, Meng
AU  - Su M
FAU - Lucast, Louise
AU  - Lucast L
FAU - Liu, Lijuan
AU  - Liu L
FAU - Netzer, William J
AU  - Netzer WJ
FAU - Gandy, Samuel E
AU  - Gandy SE
FAU - Cai, Dongming
AU  - Cai D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120914
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amyloid)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Hydrazones)
RN  - 0 (N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
RN  - EC 3.5.1.50 (Dynamin I)
SB  - IM
MH  - Amyloid/*metabolism
MH  - Amyloid Precursor Protein Secretases/genetics/*metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Amyloid beta-Protein Precursor/metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Membrane/metabolism
MH  - Dynamin I/antagonists & inhibitors/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - Gene Knockdown Techniques
MH  - Gene Silencing
MH  - Humans
MH  - Hydrazones/pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neurons/metabolism
MH  - Protein Transport
PMC - PMC3443198
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/10/02 06:00
MHDA- 2013/02/16 06:00
PMCR- 2012/09/14
CRDT- 2012/10/02 06:00
PHST- 2012/06/13 00:00 [received]
PHST- 2012/08/11 00:00 [accepted]
PHST- 2012/10/02 06:00 [entrez]
PHST- 2012/10/02 06:00 [pubmed]
PHST- 2013/02/16 06:00 [medline]
PHST- 2012/09/14 00:00 [pmc-release]
AID - PONE-D-12-17025 [pii]
AID - 10.1371/journal.pone.0045033 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(9):e45033. doi: 10.1371/journal.pone.0045033. Epub 2012 Sep 14.