PMID- 24205136
OWN - NLM
STAT- MEDLINE
DCOM- 20140918
LR  - 20220129
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 10
DP  - 2013
TI  - AMPA receptor activation promotes non-amyloidogenic amyloid precursor protein 
      processing and suppresses neuronal amyloid-beta production.
PG  - e78155
LID - 10.1371/journal.pone.0078155 [doi]
LID - e78155
AB  - Soluble oligomeric amyloid beta peptide (Abeta) generated from processing of the 
      amyloid precursor protein (APP) plays a central role in the pathogenesis of 
      Alzheimer's Disease (AD) and through actions at glutamatergic synapses affects 
      excitability and plasticity. The physiological control of APP processing is not 
      fully understood but stimulation of synaptic NMDA receptors (NMDAR) can suppress 
      Abeta levels through an ERK-dependent increase in alpha-secretase activity. AMPA-type 
      glutamate receptors (AMPAR) couple to ERK phosphorylation independently of NMDAR 
      activation raising the possibility that stimulation of AMPAR might similarly 
      promote non-amyloidogenic APP processing. We have tested this hypothesis by 
      investigating whether AMPAR directly regulate APP processing in cultured mouse 
      cortical neurons, by analyzing APP C-terminal fragments (CTFs), soluble APP 
      (sAPP), Abeta levels, and cleavage of an APP-GAL4 reporter protein. We report that 
      direct stimulation of AMPAR increases non-amyloidogenic alpha-secretase-mediated APP 
      processing and inhibits Abeta production. Processing was blocked by the matrix 
      metalloproteinase inhibitor TAPI-1 but was only partially dependent on Ca(2+) 
      influx and ERK activity. AMPAR can therefore, be added to the repertoire of 
      receptors that couple to non-amyloidogenic APP processing at glutamatergic 
      synapses and thus pharmacological targeting of AMPAR could potentially influence 
      the development and progression of Abeta pathology in AD.
FAU - Hoey, Sarah E
AU  - Hoey SE
AD  - King's College London, Wolfson Centre for Age-Related Diseases, London, United 
      Kingdom.
FAU - Buonocore, Federica
AU  - Buonocore F
FAU - Cox, Carla J
AU  - Cox CJ
FAU - Hammond, Victoria J
AU  - Hammond VJ
FAU - Perkinton, Michael S
AU  - Perkinton MS
FAU - Williams, Robert J
AU  - Williams RJ
LA  - eng
GR  - 126/ALZS_/Alzheimer's Society/United Kingdom
GR  - MRC_/Medical Research Council/United Kingdom
GR  - BB_/Biotechnology and Biological Sciences Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131024
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Amyloid beta-Peptides/genetics/*metabolism
MH  - Amyloid beta-Protein Precursor/genetics/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Mice
MH  - Phosphorylation
MH  - Receptors, AMPA/genetics/*metabolism
MH  - Receptors, N-Methyl-D-Aspartate/genetics/metabolism
PMC - PMC3813448
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/11/10 06:00
MHDA- 2014/09/19 06:00
PMCR- 2013/10/24
CRDT- 2013/11/09 06:00
PHST- 2013/08/29 00:00 [received]
PHST- 2013/09/17 00:00 [accepted]
PHST- 2013/11/09 06:00 [entrez]
PHST- 2013/11/10 06:00 [pubmed]
PHST- 2014/09/19 06:00 [medline]
PHST- 2013/10/24 00:00 [pmc-release]
AID - PONE-D-13-35877 [pii]
AID - 10.1371/journal.pone.0078155 [doi]
PST - epublish
SO  - PLoS One. 2013 Oct 24;8(10):e78155. doi: 10.1371/journal.pone.0078155. 
      eCollection 2013.