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Dynamic alteration of neprilysin and endothelin-converting enzyme in age-dependent APPswe/PS1dE9 mouse model of Alzheimer's disease.

Abstract Imbalance of Aβ production and Aβ removal leads to Aβ accumulation. Aβ degrading enzyme (including neprilysin-NEP, endothelin converting enzyme-ECE) as a therapeutic strategy for lowering brain Aβ deposition has attracted increasing attention. In this study, we investigated alteration of age and region-dependent in APP/PS1 double transgenic mice (3, 6, 9, 12 months) and their age-matched wild type mice including the ability of spatial memory, Aβ deposits, the protein expression, location and activity of NEP and ECE. Our data demonstrated that, as compared with wild type mice, APP/PS1 mice displayed significant cognitive deficit at 9 month revealed by obviously longer in the latency and distance to find the platform and shorter in time spent and swimming distance in the target quadrant. Aβ40 and Aβ42 levels exhibited a significant increase with age in the cerebral cortex and hippocampus of APP/PS1 mice after 6 month, compared with their age-matched wild type mice. And Aβ42 levels were significantly higher than Aβ40 levels in the same age of APP/PS1 mice. Furthermore, NEP protein and activity displayed a marked decrease with age in the cerebral cortex and hippocampus of APP/PS1 mice older than 6 month. Slightly different from NEP, ECE protein was up-regulated with age, while ECE activity showed a significantly decrease with age in cortex and hippocampus of APP/PS1 mice older than 6 month. Double immunofluorescence staining also demonstrated that ECE and NEP highly colocalized in cytoplasmic and membrane, and ECE immunoreactivity tended to increase with age in APP/PS1 mice, especially 12 month APP/PS1 mice. Correlation analysis showed the negative correlation between enzyme (NEP or ECE) activity and Aβ levels in the cerebral cortex and hippocampus of APP/PS1 mice, which was correlated with Aβ accumulation. These results indicate NEP rather than ECE plays more important role in resisting Aβ accumulation. The compensatory upregulation of NEP and ECE could balance Aβ metabolism and protect neuronal functions in infant and juvenile mice. These evidence might provide some clues for the treatment of Alzheimer's disease.
PMID
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Authors

Mayor MeshTerms
Keywords

Alzheimer’s disease

colocalization

endothelin converting enzyme

enzyme activity

neprilysin

Journal Title american journal of translational research
Publication Year Start




PMID- 28123645
OWN - NLM
STAT- PubMed-not-MEDLINE
DA  - 20170126
LR  - 20170220
VI  - 9
IP  - 1
DP  - 2017
TI  - Dynamic alteration of neprilysin and endothelin-converting enzyme in
      age-dependent APPswe/PS1dE9 mouse model of Alzheimer's disease.
PG  - 184-196
AB  - Imbalance of Abeta production and Abeta removal leads to Abeta accumulation.
      Abeta degrading enzyme (including neprilysin-NEP, endothelin converting
      enzyme-ECE) as a therapeutic strategy for lowering brain Abeta deposition has
      attracted increasing attention. In this study, we investigated alteration of age 
      and region-dependent in APP/PS1 double transgenic mice (3, 6, 9, 12 months) and
      their age-matched wild type mice including the ability of spatial memory, Abeta
      deposits, the protein expression, location and activity of NEP and ECE. Our data 
      demonstrated that, as compared with wild type mice, APP/PS1 mice displayed
      significant cognitive deficit at 9 month revealed by obviously longer in the
      latency and distance to find the platform and shorter in time spent and swimming 
      distance in the target quadrant. Abeta40 and Abeta42 levels exhibited a
      significant increase with age in the cerebral cortex and hippocampus of APP/PS1
      mice after 6 month, compared with their age-matched wild type mice. And Abeta42
      levels were significantly higher than Abeta40 levels in the same age of APP/PS1
      mice. Furthermore, NEP protein and activity displayed a marked decrease with age 
      in the cerebral cortex and hippocampus of APP/PS1 mice older than 6 month.
      Slightly different from NEP, ECE protein was up-regulated with age, while ECE
      activity showed a significantly decrease with age in cortex and hippocampus of
      APP/PS1 mice older than 6 month. Double immunofluorescence staining also
      demonstrated that ECE and NEP highly colocalized in cytoplasmic and membrane, and
      ECE immunoreactivity tended to increase with age in APP/PS1 mice, especially 12
      month APP/PS1 mice. Correlation analysis showed the negative correlation between 
      enzyme (NEP or ECE) activity and Abeta levels in the cerebral cortex and
      hippocampus of APP/PS1 mice, which was correlated with Abeta accumulation. These 
      results indicate NEP rather than ECE plays more important role in resisting Abeta
      accumulation. The compensatory upregulation of NEP and ECE could balance Abeta
      metabolism and protect neuronal functions in infant and juvenile mice. These
      evidence might provide some clues for the treatment of Alzheimer's disease.
FAU - Zhou, Li
AU  - Zhou L
AD  - Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
      University of Science and Technology 130 Meilong Road, Shanghai 200237, China.
FAU - Liu, Jianxu
AU  - Liu J
AD  - Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
      University of Science and Technology 130 Meilong Road, Shanghai 200237, China.
FAU - Dong, Dong
AU  - Dong D
AD  - Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
      University of Science and Technology 130 Meilong Road, Shanghai 200237, China.
FAU - Wei, Chunsheng
AU  - Wei C
AD  - Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
      University of Science and Technology 130 Meilong Road, Shanghai 200237, China.
FAU - Wang, Rui
AU  - Wang R
AD  - Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
      University of Science and Technology 130 Meilong Road, Shanghai 200237, China.
LA  - eng
PT  - Journal Article
DEP - 20170115
PL  - United States
TA  - Am J Transl Res
JT  - American journal of translational research
JID - 101493030
PMC - PMC5250715
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Abeta
OT  - colocalization
OT  - endothelin converting enzyme
OT  - enzyme activity
OT  - neprilysin
EDAT- 2017/01/27 06:00
MHDA- 2017/01/27 06:01
CRDT- 2017/01/27 06:00
PHST- 2016/06/02 [received]
PHST- 2016/08/01 [accepted]
PST - epublish
SO  - Am J Transl Res. 2017 Jan 15;9(1):184-196. eCollection 2017.

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