PMID- 34693295
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211028
IS  - 2643-4539 (Electronic)
IS  - 2643-4539 (Linking)
VI  - 4
IP  - 1
DP  - 2021
TI  - Fragmentation of Apolipoprotein E4 is Required for Differential Expression of 
      Inflammation and Activation Related Genes in Microglia Cells.
LID - 020 [pii]
LID - 10.23937/2643-4539/1710020 [doi]
AB  - The apolipoprotein E4 (APOE4) allele represents the single greatest risk factor 
      for late-onset Alzheimer's disease (AD) and accumulating evidence suggests that 
      fragmentation with a toxic-gain of function may be a key molecular step 
      associated with this risk. Recently, we demonstrated strong immunoreactivity of a 
      151 amino-terminal fragment of apoE4 (E4-fragment) within the nucleus of 
      microglia in the human AD brain. In vitro, this fragment led to toxicity and 
      activation of inflammatory processes in BV2 microglia cells. Additionally, a 
      transcriptome analysis following exogenous treatment of BV2 microglia cells with 
      this E4 fragment led to a > 2-fold up regulation of 1,608 genes, with many genes 
      playing a role in inflammation and microglia activation. To extend these 
      findings, we here report a similar transcriptome analysis in BV2 microglia cells 
      following treatment with full-length ApoE4 (FL-ApoE4). The results indicated that 
      full-length ApoE4 had a very small effect on gene expression compared to the 
      fragment. Only 48 differentially expressed genes (DEGs) were identified (p < 
      0.05, and greater than 2-fold change). A gene ontology analysis of these DEGs 
      indicated that they are not involved in inflammatory and activation processes, in 
      contrast to the genes up regulated by the E4-fragment. In addition, genes that 
      showed a negative fold-change upon FL-E4 treatment typically showed a strong 
      positive fold-change upon treatment with the fragment (Pearson's r = -0.7). Taken 
      together, these results support the hypothesis that a key step in the conversion 
      of microglia to an activated phenotype is proteolytic cleavage of FL-ApoE4. 
      Therefore, the neutralization of this amino-terminal fragment of ApoE4, 
      specifically, may serve as an important therapeutic strategy in the treatment of 
      AD.
FAU - Rohn, Troy T
AU  - Rohn TT
AD  - Department of Biological Sciences, Boise State University, USA.
FAU - Beck, James D
AU  - Beck JD
AD  - Department of Biological Sciences, Boise State University, USA.
FAU - Galla, Stephanie J
AU  - Galla SJ
AD  - Department of Biological Sciences, Boise State University, USA.
FAU - Isho, Noail F
AU  - Isho NF
AD  - University of Washington School of Medicine, University of Washington, USA.
FAU - Pollock, Tanner B
AU  - Pollock TB
AD  - Department of Biological Sciences, Boise State University, USA.
FAU - Suresh, Tarun
AU  - Suresh T
AD  - Department of Biological Sciences, Boise State University, USA.
FAU - Kulkarni, Arni
AU  - Kulkarni A
AD  - Department of Biological Sciences, Boise State University, USA.
FAU - Sanghal, Tanya
AU  - Sanghal T
AD  - Department of Biological Sciences, Boise State University, USA.
FAU - Hayden, Eric J
AU  - Hayden EJ
AD  - Department of Biological Sciences, Boise State University, USA.
LA  - eng
GR  - P20 GM103408/GM/NIGMS NIH HHS/United States
GR  - P20 GM109095/GM/NIGMS NIH HHS/United States
GR  - R15 AG042781/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20210910
PL  - United States
TA  - Int J Neurodegener Dis
JT  - International journal of neurodegenerative disorders
JID - 101723137
PMC - PMC8529910
MID - NIHMS1745767
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Apolipoprotein E4
OT  - BV2 cells
OT  - Fragment of ApoE4
OT  - Inflammation
OT  - Microglia cells
OT  - RNA-seq
OT  - Toxicity
OT  - Transcriptome analysis
COIS- Conflicts of Interest The authors declare that the research was conducted in the 
      absence of any commercial or financial relationships that could be construed as a 
      potential conflict of interest.
EDAT- 2021/10/26 06:00
MHDA- 2021/10/26 06:01
PMCR- 2021/10/21
CRDT- 2021/10/25 06:47
PHST- 2021/10/25 06:47 [entrez]
PHST- 2021/10/26 06:00 [pubmed]
PHST- 2021/10/26 06:01 [medline]
PHST- 2021/10/21 00:00 [pmc-release]
AID - 020 [pii]
AID - 10.23937/2643-4539/1710020 [doi]
PST - ppublish
SO  - Int J Neurodegener Dis. 2021;4(1):020. doi: 10.23937/2643-4539/1710020. Epub 2021 
      Sep 10.