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Transcriptome Analyses in BV2 Microglial Cells Following Treatment With Amino-Terminal Fragments of Apolipoprotein E
Tanner B Pollock1, Giovan N Cholico1, Noail F Isho2
1Department of Biological Sciences, Boise State University, Boise, ID, United States.
Frontiers in Aging Neuroscience
|September 14, 2020
Summary
The apolipoprotein E4 (APOE4) allele increases Alzheimer's disease risk. A nuclear fragment of APOE4, nApoE4, activates microglial genes involved in inflammation, suggesting a mechanism for APOE4-linked dementia.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- The apolipoprotein E4 (APOE4) allele is the primary genetic risk factor for late-onset Alzheimer's disease (AD).
- The precise mechanisms by which APOE4 contributes to AD pathogenesis remain largely unknown.
- Previous research indicated that an amino-terminal fragment of APOE4 (nApoE4) localizes to the nucleus of microglia in AD brains and induces toxicity.
Purpose of the Study:
- To investigate the specific genes and pathways affected by the nuclear fragment of APOE4 (nApoE4) in microglial cells.
- To compare the effects of nApoE4 with a similar fragment from APOE3 (nApoE3) to understand APOE4-specific mechanisms.
Main Methods:
- Transcriptome analysis (RNA sequencing) was performed on BV2 microglial cells treated with sublethal doses of nApoE4 and nApoE3.
- Gene expression profiles were analyzed to identify upregulated genes and enriched signaling pathways.
- Differential gene expression analysis was conducted to identify unique genes affected by each fragment.
Main Results:
- Treatment with nApoE4 significantly upregulated nearly 4,000 genes in BV2 cells, with 20 genes showing 182- to 715-fold increases.
- The majority of highly upregulated genes by nApoE4 are associated with immune response and M1 microglial activation.
- Both nApoE3 and nApoE4 upregulated pathways including Toll receptor signaling, chemokine/cytokine signaling, and apoptosis; however, nApoE4 uniquely upregulated fewer genes, many with unknown functions, while nApoE3 upregulated more genes involved in physiological microglial functions.
Conclusions:
- nApoE4 fragment significantly alters microglial gene expression, promoting an inflammatory M1 phenotype.
- While nApoE3 fragment appears to have more physiological roles, nApoE4 fragment may drive disease-associated inflammation in Alzheimer's disease.
- These findings support the hypothesis that APOE4 increases dementia risk through enhanced microglial inflammation.
