PMID- 15585341
OWN - NLM
STAT- MEDLINE
DCOM- 20050314
LR  - 20220330
IS  - 0197-4580 (Print)
IS  - 0197-4580 (Linking)
VI  - 26
IP  - 1
DP  - 2005 Jan
TI  - Secreted beta-amyloid precursor protein activates microglia via JNK and p38-MAPK.
PG  - 9-16
AB  - Reactive microglia are thought to play a role in the pathogenesis of Alzheimer's 
      disease (AD) and are localized to the senile plaques that are associated with 
      cognitive decline. The beta-amyloid precursor protein (betaAPP) is over-expressed 
      in the dystrophic neurites near such plaques, and secreted forms of betaAPP 
      (sAPPalpha) activate inflammatory responses in microglia. To characterize the 
      mechanisms by which sAPPalpha activates microglia, we assayed its effects on MAP 
      kinases, including c-Jun N-terminal kinases (JNK), extracellular signal-regulated 
      protein kinases (ERK), and p38-MAPK. sAPPalpha was found to rapidly activate 
      JNKs, ERKs and p38-MAPK in a dose-dependent manner. The JNK inhibitor SP600125 
      and the p38 inhibitor SB203580 independently reduced both nitrite accumulation 
      and induction of inflammatory nitric oxide synthase (iNOS). By contrast, 
      inhibition of the ERK pathway with U0126 did not appreciably affect either 
      outcome measure. These findings suggest that sAPP activates the ERK, JNK and p38 
      classes of MAP kinases but that only JNK and p38-MAPK are critical for activation 
      of microglia by sAPPalpha, a process that compromises neuronal function and 
      survival.
FAU - Bodles, Angela M
AU  - Bodles AM
AD  - Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical 
      Sciences, Little Rock, AR 72205, USA.
FAU - Barger, Steven W
AU  - Barger SW
LA  - eng
GR  - AG12411/AG/NIA NIH HHS/United States
GR  - AG17498/AG/NIA NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neurobiol Aging
JT  - Neurobiology of aging
JID - 8100437
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Anthracenes)
RN  - 0 (Butadienes)
RN  - 0 (Drug Combinations)
RN  - 0 (Imidazoles)
RN  - 0 (Nitriles)
RN  - 0 (Nitrites)
RN  - 0 (Pyridines)
RN  - 0 (U 0126)
RN  - 1TW30Y2766 (pyrazolanthrone)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - OU13V1EYWQ (SB 203580)
SB  - IM
MH  - Amyloid beta-Protein Precursor/*pharmacology
MH  - Animals
MH  - Animals, Newborn
MH  - Anthracenes/pharmacology
MH  - Blotting, Western/methods
MH  - Butadienes/pharmacology
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Drug Combinations
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism
MH  - Imidazoles/pharmacology
MH  - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Microglia/*drug effects
MH  - Nitriles/pharmacology
MH  - Nitrites/metabolism
MH  - Pyridines/pharmacology
MH  - Rats
MH  - Time Factors
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
EDAT- 2004/12/09 09:00
MHDA- 2005/03/15 09:00
CRDT- 2004/12/09 09:00
PHST- 2003/05/16 00:00 [received]
PHST- 2003/12/18 00:00 [revised]
PHST- 2004/02/18 00:00 [accepted]
PHST- 2004/12/09 09:00 [pubmed]
PHST- 2005/03/15 09:00 [medline]
PHST- 2004/12/09 09:00 [entrez]
AID - S0197458004001253 [pii]
AID - 10.1016/j.neurobiolaging.2004.02.022 [doi]
PST - ppublish
SO  - Neurobiol Aging. 2005 Jan;26(1):9-16. doi: 10.1016/j.neurobiolaging.2004.02.022.