PMID- 36766752
OWN - NLM
STAT- MEDLINE
DCOM- 20230214
LR  - 20240216
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 12
IP  - 3
DP  - 2023 Jan 25
TI  - Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging 
      Supports a Warburg Neuroprotective Cascade against Alzheimer's Disease.
LID - 10.3390/cells12030410 [doi]
LID - 410
AB  - Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for 
      late-onset Alzheimer's disease (LOAD), whereas ApoE2 reduces the risk for LOAD. 
      The underlying mechanisms are unclear but may include effects on brain energy 
      metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE 
      isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE 
      knock-in mouse models to investigate relationships among ApoE isoforms, 
      glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells 
      retained robust hexokinase (HK) expression and glycolytic activity, whereas these 
      endpoints progressively declined with aging in ApoE4-expressing cells. These 
      divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers 
      of cellular wellness. Moreover, ApoE4-expressing cells upregulated 
      phosphofructokinase and pyruvate kinase with the apparent intent of compensating 
      for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK 
      levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively 
      regulated by ApoE isoforms but was only partially responsible for the 
      ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE 
      isoforms differentially modulate neuronal glycolysis through HK regulation, with 
      ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal 
      health during aging. These findings lend compelling support to the emerging 
      inverse-Warburg theory of AD and highlight a therapeutic opportunity for 
      bolstering brain glycolytic resilience to prevent and treat AD.
FAU - Zhang, Xin
AU  - Zhang X
AUID- ORCID: 0000-0002-8525-3597
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, University of 
      Kansas, Lawrence, KS 66045, USA.
FAU - Wu, Long
AU  - Wu L
AUID- ORCID: 0000-0003-1165-1784
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, University of 
      Kansas, Lawrence, KS 66045, USA.
FAU - Swerdlow, Russell H
AU  - Swerdlow RH
AD  - Department of Neurology, University of Kansas Medical Center, Kansas City, KS 
      66160, USA.
FAU - Zhao, Liqin
AU  - Zhao L
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, University of 
      Kansas, Lawrence, KS 66045, USA.
AD  - Neuroscience Graduate Program, University of Kansas, Lawrence, KS 66045, USA.
LA  - eng
GR  - P30 AG072973/AG/NIA NIH HHS/United States
GR  - R01 AG061038/AG/NIA NIH HHS/United States
GR  - R01 AG071682/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230125
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Apolipoprotein E2)
RN  - 0 (Apolipoprotein E4)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Protein Isoforms)
SB  - IM
MH  - Mice
MH  - Humans
MH  - Animals
MH  - Apolipoprotein E2/genetics/metabolism
MH  - *Apolipoprotein E4/genetics/metabolism
MH  - *Alzheimer Disease/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Apolipoproteins E/genetics
MH  - Glycolysis
MH  - Aging
MH  - Protein Isoforms/metabolism
PMC - PMC9914046
OTO - NOTNLM
OT  - ApoE2
OT  - ApoE4
OT  - Warburg effect
OT  - apolipoprotein E
OT  - brain resilience
OT  - glycolysis
OT  - hexokinase
OT  - late-onset Alzheimer's disease (LOAD)
COIS- The authors declare no conflict of interest.
EDAT- 2023/02/12 06:00
MHDA- 2023/02/15 06:00
PMCR- 2023/01/25
CRDT- 2023/02/11 01:09
PHST- 2022/08/08 00:00 [received]
PHST- 2023/01/20 00:00 [revised]
PHST- 2023/01/23 00:00 [accepted]
PHST- 2023/02/11 01:09 [entrez]
PHST- 2023/02/12 06:00 [pubmed]
PHST- 2023/02/15 06:00 [medline]
PHST- 2023/01/25 00:00 [pmc-release]
AID - cells12030410 [pii]
AID - cells-12-00410 [pii]
AID - 10.3390/cells12030410 [doi]
PST - epublish
SO  - Cells. 2023 Jan 25;12(3):410. doi: 10.3390/cells12030410.