PMID- 35023380
OWN - NLM
STAT- MEDLINE
DCOM- 20220413
LR  - 20240214
IS  - 1559-7016 (Electronic)
IS  - 0271-678X (Print)
IS  - 0271-678X (Linking)
VI  - 42
IP  - 5
DP  - 2022 May
TI  - Apolipoprotein E epsilon4/4 genotype limits response to dietary induction of 
      hyperhomocysteinemia and resulting inflammatory signaling.
PG  - 771-787
LID - 10.1177/0271678X211069006 [doi]
AB  - Vascular contributions to cognitive impairment and dementia (VCID) are the second 
      leading cause of dementia behind Alzheimer's disease. Apolipoprotein E (ApoE) is 
      a lipid transporting lipoprotein found within the brain and periphery. The APOE 
      epsilon4 allele is the strongest genetic risk factor for late onset Alzheimer's disease 
      and is a risk factor for VCID. Our lab has previously utilized a dietary model of 
      hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in 
      mice. This diet induces perivascular inflammation through cumulative oxidative 
      damage leading to glial mediated inflammation and blood brain barrier breakdown. 
      Here, we examine the impact of ApoE epsilon4 compared to epsilon3 alleles on the progression 
      of VCID pathology and inflammation in our dietary model of HHcy. We report a 
      significant resistance to HHcy induction in epsilon4 mice, accompanied by a number of 
      related differences related to homocysteine (Hcy) metabolism and methylation 
      cycle, or 1-C, metabolites. There were also significant differences in 
      inflammatory profiles between epsilon3 and epsilon4 mice, as well as significant reduction in 
      Serpina3n, a serine protease inhibitor associated with ApoE epsilon4, expression in epsilon4 
      HHcy mice relative to epsilon4 controls. Finally, we find evidence of pervasive sex 
      differences within both genotypes in response to HHcy induction.
FAU - Seaks, Charles E
AU  - Seaks CE
AUID- ORCID: 0000-0002-4124-7865
AD  - Sanders-Brown Center on Aging, Lexington, KY, USA.
AD  - Department of Physiology, University of Kentucky, Lexington, KY, USA.
FAU - Weekman, Erica M
AU  - Weekman EM
AD  - Sanders-Brown Center on Aging, Lexington, KY, USA.
AD  - Department of Physiology, University of Kentucky, Lexington, KY, USA.
FAU - Sudduth, Tiffany L
AU  - Sudduth TL
AD  - Sanders-Brown Center on Aging, Lexington, KY, USA.
FAU - Xie, Kevin
AU  - Xie K
AD  - Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
FAU - Wasek, Brandi
AU  - Wasek B
AD  - Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White 
      Research Institute, Dallas, TX, USA.
FAU - Fardo, David W
AU  - Fardo DW
AD  - Sanders-Brown Center on Aging, Lexington, KY, USA.
AD  - Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
FAU - Johnson, Lance A
AU  - Johnson LA
AD  - Sanders-Brown Center on Aging, Lexington, KY, USA.
AD  - Department of Physiology, University of Kentucky, Lexington, KY, USA.
FAU - Bottiglieri, Teodoro
AU  - Bottiglieri T
AD  - Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White 
      Research Institute, Dallas, TX, USA.
FAU - Wilcock, Donna M
AU  - Wilcock DM
AD  - Sanders-Brown Center on Aging, Lexington, KY, USA.
AD  - Department of Physiology, University of Kentucky, Lexington, KY, USA.
LA  - eng
GR  - R56 AG057191/AG/NIA NIH HHS/United States
GR  - P30 AG072946/AG/NIA NIH HHS/United States
GR  - R01 AG062550/AG/NIA NIH HHS/United States
GR  - RF1 AG057754/AG/NIA NIH HHS/United States
GR  - R01 NS097722/NS/NINDS NIH HHS/United States
GR  - R01 AG060056/AG/NIA NIH HHS/United States
GR  - T32 NS077889/NS/NINDS NIH HHS/United States
GR  - T32 GM118292/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20220113
PL  - United States
TA  - J Cereb Blood Flow Metab
JT  - Journal of cerebral blood flow and metabolism : official journal of the 
      International Society of Cerebral Blood Flow and Metabolism
JID - 8112566
RN  - 0 (Apolipoprotein E3)
RN  - 0 (Apolipoprotein E4)
SB  - IM
MH  - Alleles
MH  - *Alzheimer Disease/genetics
MH  - Animals
MH  - Apolipoprotein E3/genetics
MH  - *Apolipoprotein E4/genetics
MH  - *Dementia, Vascular/genetics
MH  - Diet
MH  - Female
MH  - Gene Knock-In Techniques
MH  - Genotype
MH  - Humans
MH  - *Hyperhomocysteinemia/genetics
MH  - Inflammation/genetics
MH  - Male
MH  - Mice
PMC - PMC9254035
OTO - NOTNLM
OT  - APOE
OT  - SERPIN
OT  - VCID
OT  - inflammation
OT  - metabolism
COIS- Declaration of conflicting interests: The author(s) declared no potential 
      conflicts of interest with respect to the research, authorship, and/or 
      publication of this article.
EDAT- 2022/01/14 06:00
MHDA- 2022/04/14 06:00
PMCR- 2023/01/13
CRDT- 2022/01/13 08:41
PHST- 2022/01/14 06:00 [pubmed]
PHST- 2022/04/14 06:00 [medline]
PHST- 2022/01/13 08:41 [entrez]
PHST- 2023/01/13 00:00 [pmc-release]
AID - 10.1177_0271678X211069006 [pii]
AID - 10.1177/0271678X211069006 [doi]
PST - ppublish
SO  - J Cereb Blood Flow Metab. 2022 May;42(5):771-787. doi: 10.1177/0271678X211069006. 
      Epub 2022 Jan 13.