PMID- 27902456
OWN - NLM
STAT- MEDLINE
DCOM- 20171106
LR  - 20211204
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 8
IP  - 11
DP  - 2016 Nov 29
TI  - Long-term caloric restriction in ApoE-deficient mice results in neuroprotection 
      via Fgf21-induced AMPK/mTOR pathway.
PG  - 2777-2789
LID - 10.18632/aging.101086 [doi]
AB  - Caloric restriction (CR) decelerates the aging process, extends lifespan and 
      exerts neuroprotective effects in diverse species by so far unknown mechanisms. 
      Based on known neuroprotective effects of fibroblastic growth factor 21 (Fgf21) 
      we speculate that CR upregulates Fgf21, which phosphorylates neuronal 
      AMP-activated protein kinase (AMPK), leading to a decrease of mammalian target of 
      rapamycin (mTOR) signaling activity and an inhibition of 
      tau-hyperphosphorylation. This in turn reduces the formation of neurofibrillary 
      tangles, a neuropathological hallmark of Alzheimer s disease. ApoE-deficient mice 
      (ApoE-/-), serving as a model of neurodegeneration, showed upon CR vs. ad libitum 
      feeding increased Fgf21 levels in both, plasma and brain as well as higher 
      phosphorylation of fibroblastic growth factor receptor 1c (Fgfr1c), extracellular 
      signal-regulated kinases 1/2 (ERK1/2) and AMPK in brain, lower activity of mTOR 
      and decreased Tau-phosphorylation. Finally, CR in ApoE-/- mice caused 
      neuroprotection as indicated by a higher synaptic plasticity shown by 
      immunohistochemical analysis with increased numbers of PSD95-positive neurons and 
      a better cognitive performance as analyzed with Morris water maze test. These 
      data provide substantial evidence that neuroprotection upon CR seems to be 
      Fgf21-dependent. Further experiments are necessary to evaluate Fgf21 as a 
      therapeutic tool to treat tauopathy for improvement of cognitive performance.
FAU - Ruhlmann, Claire
AU  - Ruhlmann C
AD  - Institute for Experimental Surgery, Rostock University Medical Center, 18057 
      Rostock, Germany.
FAU - Wolk, Tjark
AU  - Wolk T
AD  - Institute for Experimental Surgery, Rostock University Medical Center, 18057 
      Rostock, Germany.
FAU - Blumel, Tobias
AU  - Blumel T
AD  - Institute for Experimental Surgery, Rostock University Medical Center, 18057 
      Rostock, Germany.
FAU - Stahn, Laura
AU  - Stahn L
AD  - Institute for Experimental Surgery, Rostock University Medical Center, 18057 
      Rostock, Germany.
FAU - Vollmar, Brigitte
AU  - Vollmar B
AD  - Institute for Experimental Surgery, Rostock University Medical Center, 18057 
      Rostock, Germany.
FAU - Kuhla, Angela
AU  - Kuhla A
AD  - Institute for Experimental Surgery, Rostock University Medical Center, 18057 
      Rostock, Germany.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
RN  - 0 (Apolipoproteins E)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - 0 (fibroblast growth factor-21 receptor, mouse)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Aging/*physiology
MH  - Alzheimer Disease
MH  - Animals
MH  - Apolipoproteins E/*deficiency
MH  - *Caloric Restriction
MH  - Cognition
MH  - Disease Models, Animal
MH  - Female
MH  - Maze Learning
MH  - Mice
MH  - Neurofibrillary Tangles
MH  - Neuroprotection/genetics/*physiology
MH  - Receptors, Fibroblast Growth Factor/genetics/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Up-Regulation
PMC - PMC5191869
OTO - NOTNLM
OT  - Alzheimer s disease
OT  - Fgf21
OT  - Tau-phosphorylation
OT  - caloric restriction
OT  - deficiency ApoE-
OT  - mTOR
OT  - pAMPK
COIS- The other authors declare that they have no conflict of interest.
EDAT- 2016/12/03 06:00
MHDA- 2017/11/07 06:00
PMCR- 2016/11/01
CRDT- 2016/12/01 06:00
PHST- 2016/07/01 00:00 [received]
PHST- 2016/11/14 00:00 [accepted]
PHST- 2016/12/03 06:00 [pubmed]
PHST- 2017/11/07 06:00 [medline]
PHST- 2016/12/01 06:00 [entrez]
PHST- 2016/11/01 00:00 [pmc-release]
AID - 101086 [pii]
AID - 10.18632/aging.101086 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2016 Nov 29;8(11):2777-2789. doi: 10.18632/aging.101086.