PMID- 20864542
OWN - NLM
STAT- MEDLINE
DCOM- 20101230
LR  - 20230815
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 48
DP  - 2010 Nov 26
TI  - Macroautophagy is not directly involved in the metabolism of amyloid precursor 
      protein.
PG  - 37415-26
LID - 10.1074/jbc.M110.186411 [doi]
AB  - Alterations in the metabolism of amyloid precursor protein (APP) are believed to 
      play a central role in Alzheimer disease pathogenesis. Burgeoning data indicate 
      that APP is proteolytically processed in endosomal-autophagic-lysosomal 
      compartments. In this study, we used both in vivo and in vitro paradigms to 
      determine whether alterations in macroautophagy affect APP metabolism. Three 
      mouse models of glycosphingolipid storage diseases, namely Niemann-Pick type C1, 
      GM1 gangliosidosis, and Sandhoff disease, had mTOR-independent increases in the 
      autophagic vacuole (AV)-associated protein, LC3-II, indicative of impaired 
      lysosomal flux. APP C-terminal fragments (APP-CTFs) were also increased in brains 
      of the three mouse models; however, discrepancies between LC3-II and APP-CTFs 
      were seen between primary (GM1 gangliosidosis and Sandhoff disease) and secondary 
      (Niemann-Pick type C1) lysosomal storage models. APP-CTFs were proportionately 
      higher than LC3-II in cerebellar regions of GM1 gangliosidosis and Sandhoff 
      disease, although LC3-II increased before APP-CTFs in brains of NPC1 mice. 
      Endogenous murine Abeta40 from RIPA-soluble extracts was increased in brains of all 
      three mice. The in vivo relationship between AV and APP-CTF accumulation was also 
      seen in cultured neurons treated with agents that impair primary (chloroquine and 
      leupeptin + pepstatin) and secondary (U18666A and vinblastine) lysosomal flux. 
      However, Abeta secretion was unaffected by agents that induced autophagy (rapamycin) 
      or impaired AV clearance, and LC3-II-positive AVs predominantly co-localized with 
      degradative LAMP-1-positive lysosomes. These data suggest that neuronal 
      macroautophagy does not directly regulate APP metabolism but highlights the 
      important anti-amyloidogenic role of lysosomal proteolysis in post-secretase 
      APP-CTF catabolism.
FAU - Boland, Barry
AU  - Boland B
AD  - Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical 
      Science, Conway Institute, University College Dublin, Dublin 4, Ireland. 
      barry.boland@ucd.ie
FAU - Smith, David A
AU  - Smith DA
FAU - Mooney, Declan
AU  - Mooney D
FAU - Jung, Sonia S
AU  - Jung SS
FAU - Walsh, Dominic M
AU  - Walsh DM
FAU - Platt, Frances M
AU  - Platt FM
LA  - eng
GR  - 069883/B/02/Z/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100923
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amyloid beta-Protein Precursor)
SB  - IM
MH  - Alzheimer Disease/genetics/metabolism/*physiopathology
MH  - Amyloid beta-Protein Precursor/chemistry/genetics/*metabolism
MH  - Animals
MH  - *Autophagy
MH  - Brain/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Lysosomes/chemistry/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Neurons/cytology/metabolism
MH  - Protein Structure, Tertiary
PMC - PMC2988347
EDAT- 2010/09/25 06:00
MHDA- 2010/12/31 06:00
PMCR- 2010/09/23
CRDT- 2010/09/25 06:00
PHST- 2010/09/25 06:00 [entrez]
PHST- 2010/09/25 06:00 [pubmed]
PHST- 2010/12/31 06:00 [medline]
PHST- 2010/09/23 00:00 [pmc-release]
AID - S0021-9258(20)46717-1 [pii]
AID - M110.186411 [pii]
AID - 10.1074/jbc.M110.186411 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Nov 26;285(48):37415-26. doi: 10.1074/jbc.M110.186411. Epub 
      2010 Sep 23.