PMID- 37385335
OWN - NLM
STAT- MEDLINE
DCOM- 20230819
LR  - 20231003
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Print)
IS  - 0306-4522 (Linking)
VI  - 526
DP  - 2023 Aug 21
TI  - Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer's 
      Disease Hippocampal CA1 Stratum Radiatum.
PG  - 204-222
LID - S0306-4522(23)00289-0 [pii]
LID - 10.1016/j.neuroscience.2023.06.019 [doi]
AB  - Current data suggest a hypothesis of vascular pathogenesis for the development 
      and progression of Alzheimer's disease (AD). To investigate this, we studied the 
      association of apolipoprotein E4 (APOE4) gene on microvessels in human 
      autopsy-confirmed AD with and without APOE4, compared with age/sex-matched 
      control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) 
      had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) 
      and endothelial cell density, reflecting aging progression. In AD + APOE4, an 
      increase in strong oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine 
      (8-OHdG), VEGF, and endothelial cell density were associated with increased 
      diameter of arterioles and perivascular space dilation. In cultured human brain 
      microvascular cells (HBMECs), treatment of ApoE4 protein plus amyloid-beta (Abeta) 
      oligomers increased superoxide production and the apoptotic marker cleaved 
      caspase 3, sustained hypoxia inducible factor-1alpha (HIF-1alpha) stability that was 
      associated with an increase in MnSOD, VEGF, and cell density. This cell 
      over-proliferation was inhibited with the antioxidants N-acetyl cysteine and 
      MnTMPyP, the HIF-1alpha inhibitor echinomycin, the VEGFR-2 receptor blocker SU1498, 
      the protein kinase C (PKC) epsilon knock-down (KD) and the extracellular 
      signal-regulated kinase 1/2 (ERK) inhibitor FR180204. The PKCepsilon KD and echinomycin 
      decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in 
      hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, 
      while those in APOE4 carriers with AD are related with pathogenesis of 
      cerebrovascular disease.
CI  - Copyright (c) 2023 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Wang, Huaixing
AU  - Wang H
AD  - Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical 
      College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
FAU - Zhang, Zongxiu
AU  - Zhang Z
AD  - Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical 
      College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
FAU - Sittirattanayeunyong, Sorawit
AU  - Sittirattanayeunyong S
AD  - Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical 
      College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
FAU - Hongpaisan, Jarin
AU  - Hongpaisan J
AD  - Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical 
      College, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic 
      address: jarin.hongpaisan@jefferson.edu.
LA  - eng
GR  - R01 AG058884/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230628
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Apolipoprotein E4)
RN  - 0 (Apolipoproteins E)
RN  - 512-64-1 (Echinomycin)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (ApoE protein, human)
SB  - IM
MH  - Humans
MH  - *Alzheimer Disease/pathology
MH  - Amyloid beta-Peptides/metabolism
MH  - Apolipoprotein E4/genetics/metabolism
MH  - Apolipoproteins E
MH  - CA1 Region, Hippocampal/pathology
MH  - *Echinomycin/metabolism
MH  - Hippocampus/metabolism
MH  - Vascular Endothelial Growth Factor A/metabolism
PMC - PMC10528415
MID - NIHMS1914629
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - arteriolosclerosis
OT  - hippocampus
OT  - human brain microvascular cells
OT  - oxidative stress
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/06/30 01:06
MHDA- 2023/08/16 06:43
PMCR- 2024/08/21
CRDT- 2023/06/29 19:12
PHST- 2022/12/14 00:00 [received]
PHST- 2023/06/15 00:00 [revised]
PHST- 2023/06/22 00:00 [accepted]
PHST- 2024/08/21 00:00 [pmc-release]
PHST- 2023/08/16 06:43 [medline]
PHST- 2023/06/30 01:06 [pubmed]
PHST- 2023/06/29 19:12 [entrez]
AID - S0306-4522(23)00289-0 [pii]
AID - 10.1016/j.neuroscience.2023.06.019 [doi]
PST - ppublish
SO  - Neuroscience. 2023 Aug 21;526:204-222. doi: 10.1016/j.neuroscience.2023.06.019. 
      Epub 2023 Jun 28.