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The effects of exercise on hypothalamic neurodegeneration of Alzheimer's disease mouse model.

Abstract Alzheimer's disease is a neurodegenerative disorder that affects the central nervous system. In this study, we characterized and examined the early metabolic changes in the triple transgenic mouse AD model (3xtg-AD), and their relationship with the hypothalamus, a key regulator of metabolism in the central nervous system. We observed that the 3xtg-AD model exhibited significantly higher oxygen consumption as well as food intake before reported amyloid plaque formation, indicating that metabolic abnormalities occurred at early onset in the 3xtg-AD model compared with their counterparts. Analysis of gene expression in the hypothalamus indicated increased mRNA expression of inflammation- and apoptosis-related genes, as well as decreased gene expression of Agouti-related protein (AgRP) and Melanocortin 4 receptor (MC4R) at 12 weeks of age. Immunofluorescence analysis revealed that pro-opiomelanocortin (POMC) and NPY-expressing neurons decreased at 24 weeks in the 3xtg-AD model. Four weeks of voluntary exercise were sufficient to reverse the gene expression of inflammation and apoptotic markers in the hypothalamus, six weeks of exercise improved glucose metabolism, moreover, 8 weeks of voluntary exercise training attenuated apoptosis and augmented POMC and NPY-expressing neuronal populations in the hypothalamus compared to the control group. Our results indicated that early onset of metabolic abnormalities may contribute to the pathology of AD, which is associated with increased inflammation as well as decreased neuronal population and key neuropeptides in the hypothalamus. Furthermore, early intervention by voluntary exercise normalized hypothalamic inflammation and neurodegeneration as well as glucose metabolism in the 3xtg-AD model. The data, taken as a whole, suggests a hypothalamic-mediated mechanism where exercise prevents the progression of dementia and of Alzheimer's disease.
PMID
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Authors

Mayor MeshTerms

Disease Models, Animal

Physical Conditioning, Animal

Keywords
Journal Title plos one
Publication Year Start




PMID- 29293568
OWN - NLM
STAT- MEDLINE
DCOM- 20180206
LR  - 20180206
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 13
IP  - 1
DP  - 2018
TI  - The effects of exercise on hypothalamic neurodegeneration of Alzheimer's disease 
      mouse model.
PG  - e0190205
LID - 10.1371/journal.pone.0190205 [doi]
AB  - Alzheimer's disease is a neurodegenerative disorder that affects the central
      nervous system. In this study, we characterized and examined the early metabolic 
      changes in the triple transgenic mouse AD model (3xtg-AD), and their relationship
      with the hypothalamus, a key regulator of metabolism in the central nervous
      system. We observed that the 3xtg-AD model exhibited significantly higher oxygen 
      consumption as well as food intake before reported amyloid plaque formation,
      indicating that metabolic abnormalities occurred at early onset in the 3xtg-AD
      model compared with their counterparts. Analysis of gene expression in the
      hypothalamus indicated increased mRNA expression of inflammation- and
      apoptosis-related genes, as well as decreased gene expression of Agouti-related
      protein (AgRP) and Melanocortin 4 receptor (MC4R) at 12 weeks of age.
      Immunofluorescence analysis revealed that pro-opiomelanocortin (POMC) and
      NPY-expressing neurons decreased at 24 weeks in the 3xtg-AD model. Four weeks of 
      voluntary exercise were sufficient to reverse the gene expression of inflammation
      and apoptotic markers in the hypothalamus, six weeks of exercise improved glucose
      metabolism, moreover, 8 weeks of voluntary exercise training attenuated apoptosis
      and augmented POMC and NPY-expressing neuronal populations in the hypothalamus
      compared to the control group. Our results indicated that early onset of
      metabolic abnormalities may contribute to the pathology of AD, which is
      associated with increased inflammation as well as decreased neuronal population
      and key neuropeptides in the hypothalamus. Furthermore, early intervention by
      voluntary exercise normalized hypothalamic inflammation and neurodegeneration as 
      well as glucose metabolism in the 3xtg-AD model. The data, taken as a whole,
      suggests a hypothalamic-mediated mechanism where exercise prevents the
      progression of dementia and of Alzheimer's disease.
FAU - Do, Khoa
AU  - Do K
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Laing, Brenton Thomas
AU  - Laing BT
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Landry, Taylor
AU  - Landry T
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Bunner, Wyatt
AU  - Bunner W
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Mersaud, Naderi
AU  - Mersaud N
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Matsubara, Tomoko
AU  - Matsubara T
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Li, Peixin
AU  - Li P
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Yuan, Yuan
AU  - Yuan Y
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
FAU - Lu, Qun
AU  - Lu Q
AD  - Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina
      University, Greenville, North Carolina, United States of America.
AD  - The Harriet and John Wooten Laboratory for Alzheimer's and Neurodegenerative
      Diseases Research, Brody School of Medicine, East Carolina University,
      Greenville, North Carolina, United States of America.
FAU - Huang, Hu
AU  - Huang H
AD  - Department of Kinesiology, East Carolina University, Greenville, North Carolina, 
      United States of America.
AD  - East Carolina Diabetes and Obesity Institute, East Carolina University,
      Greenville, North Carolina, United States of America.
AD  - The Harriet and John Wooten Laboratory for Alzheimer's and Neurodegenerative
      Diseases Research, Brody School of Medicine, East Carolina University,
      Greenville, North Carolina, United States of America.
AD  - Department of Physiology, Brody School of Medicine, East Carolina University,
      Greenville, North Carolina, United States of America.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180102
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Biomarkers)
RN  - 66796-54-1 (Pro-Opiomelanocortin)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Alzheimer Disease/*pathology
MH  - Animals
MH  - Biomarkers/metabolism
MH  - *Disease Models, Animal
MH  - Gene Expression Regulation
MH  - Glucose/metabolism
MH  - Hypothalamus/metabolism/*pathology
MH  - In Situ Nick-End Labeling
MH  - Mice
MH  - Mice, Transgenic
MH  - Mitochondria/metabolism
MH  - *Physical Conditioning, Animal
MH  - Pro-Opiomelanocortin/metabolism
MH  - Real-Time Polymerase Chain Reaction
PMC - PMC5749759
EDAT- 2018/01/03 06:00
MHDA- 2018/02/07 06:00
CRDT- 2018/01/03 06:00
PHST- 2017/09/20 00:00 [received]
PHST- 2017/12/11 00:00 [accepted]
PHST- 2018/01/03 06:00 [entrez]
PHST- 2018/01/03 06:00 [pubmed]
PHST- 2018/02/07 06:00 [medline]
AID - 10.1371/journal.pone.0190205 [doi]
AID - PONE-D-17-34221 [pii]
PST - epublish
SO  - PLoS One. 2018 Jan 2;13(1):e0190205. doi: 10.1371/journal.pone.0190205.
      eCollection 2018.