PMID- 36215026
OWN - NLM
STAT- MEDLINE
DCOM- 20221228
LR  - 20240102
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Print)
IS  - 0893-7648 (Linking)
VI  - 60
IP  - 1
DP  - 2023 Jan
TI  - Suppression of Wnt/beta-Catenin Signaling Is Associated with Downregulation of Wnt1, 
      PORCN, and Rspo2 in Alzheimer's Disease.
PG  - 26-35
LID - 10.1007/s12035-022-03065-1 [doi]
AB  - Wnt and R-spondin (Rspo) proteins are two major types of endogenous Wnt/beta-catenin 
      signaling agonists. While Wnt/beta-catenin signaling is greatly diminished in 
      Alzheimer's disease (AD), it remains to be elucidated whether the inhibition of 
      this pathway is associated with dysregulation of Wnt and Rspo proteins. By 
      analyzing temporal cortex RNA-seq data of the human postmortem brain samples, we 
      found that WNT1 and RRPO2 were significantly downregulated in human AD brains. In 
      addition, the expression of Wnt acyltransferase porcupine (PORCN), which is 
      essential for Wnt maturation and secretion, was greatly deceased in these human 
      AD brains. Interestingly, the lowest levels of WNT1, PORCN, and RSPO2 expression 
      were found in human AD brains carrying two copies of APOE4 allele, the strongest 
      genetic risk factor of late-onset AD. Importantly, there were positive 
      correlations among the levels of WNT1, PORCN, and RSPO2 expression in human AD 
      brains. Supporting observations in humans, Wnt1, PORCN, and Rspo2 were 
      downregulated and Wnt/beta-catenin signaling was diminished in the 5xFAD amyloid 
      model mice. In human APOE-targeted replacement mice, downregulation of WNT1, 
      PORCN, and RSPO2 expression was positively associated with aging and APOE4 
      genotype. Finally, WNT1 and PORCN expression and Wnt/beta-catenin signaling were 
      inhibited in human APOE4 iPSC-derived astrocytes when compared to the isogenic 
      APOE3 iPSC-derived astrocytes. Altogether, our findings suggest that the 
      dysregulations of Wnt1, PORCN, and Rspo2 could be coordinated together to 
      diminish Wnt/beta-catenin signaling in aging- and APOE4-dependent manners in the AD 
      brain.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business 
      Media, LLC, part of Springer Nature.
FAU - Macyczko, Jesse R
AU  - Macyczko JR
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
FAU - Wang, Na
AU  - Wang N
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
FAU - Zhao, Jing
AU  - Zhao J
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
AD  - Center for Regenerative Medicine, Neuroregeneration Laboratory, Mayo Clinic, 
      Jacksonville, FL, 32224, USA.
FAU - Ren, Yingxue
AU  - Ren Y
AD  - Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, 32224, 
      USA.
FAU - Lu, Wenyan
AU  - Lu W
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
AD  - Center for Regenerative Medicine, Neuroregeneration Laboratory, Mayo Clinic, 
      Jacksonville, FL, 32224, USA.
FAU - Ikezu, Tadafumi C
AU  - Ikezu TC
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
FAU - Zhao, Na
AU  - Zhao N
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
FAU - Liu, Chia-Chen
AU  - Liu CC
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
FAU - Bu, Guojun
AU  - Bu G
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
AD  - Center for Regenerative Medicine, Neuroregeneration Laboratory, Mayo Clinic, 
      Jacksonville, FL, 32224, USA.
FAU - Li, Yonghe
AU  - Li Y
AUID- ORCID: 0000-0003-3489-6362
AD  - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA. 
      Li.Yonghe@mayo.edu.
LA  - eng
GR  - 9AZ09/Florida Department of State/
GR  - R21AG065653/GF/NIH HHS/United States
GR  - U19 AG069701/AG/NIA NIH HHS/United States
GR  - U19AG069701/GF/NIH HHS/United States
GR  - R21 AG065653/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20221010
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - EC 2.3.- (Acyltransferases)
RN  - 0 (Apolipoprotein E4)
RN  - 0 (Membrane Proteins)
RN  - EC 2.3.1.- (PORCN protein, human)
RN  - 0 (WNT1 protein, human)
RN  - 0 (Rspo2 protein, human)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Acyltransferases/metabolism
MH  - *Alzheimer Disease/genetics
MH  - Apolipoprotein E4/genetics
MH  - Down-Regulation
MH  - *Membrane Proteins/metabolism
MH  - *Wnt Signaling Pathway
MH  - *Intercellular Signaling Peptides and Proteins/metabolism
PMC - PMC9795414
MID - NIHMS1859521
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - PORCN
OT  - Rspo2
OT  - Wnt signaling
OT  - Wnt1
OT  - apoE4
COIS- Conflict of Interest: G.B. consults for SciNeuro and Lexeo, is on the scientific 
      advisory board for Kisbee, has consulted for AbbVie, E-Scape, Eisai, and Vida 
      Ventures. Other authors declare no competing interests.
EDAT- 2022/10/11 06:00
MHDA- 2022/12/21 06:00
PMCR- 2024/01/01
CRDT- 2022/10/10 11:21
PHST- 2022/05/21 00:00 [received]
PHST- 2022/10/03 00:00 [accepted]
PHST- 2022/10/11 06:00 [pubmed]
PHST- 2022/12/21 06:00 [medline]
PHST- 2022/10/10 11:21 [entrez]
PHST- 2024/01/01 00:00 [pmc-release]
AID - 10.1007/s12035-022-03065-1 [pii]
AID - 10.1007/s12035-022-03065-1 [doi]
PST - ppublish
SO  - Mol Neurobiol. 2023 Jan;60(1):26-35. doi: 10.1007/s12035-022-03065-1. Epub 2022 
      Oct 10.