Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro
Mutations to the cholesterol transport protein apolipoprotein E (ApoE) have been identified as a major risk factor for the development of sporadic or late-onset Alzheimer’s disease (AD), with the <i>e4</i> allele representing an increased risk and the rare <i>e2</i> allele ha...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | Current Issues in Molecular Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1467-3045/43/1/18 |
| _version_ | 1797521498437582848 |
|---|---|
| author | Jaclyn Iannucci Abhik Sen Paula Grammas |
| author_facet | Jaclyn Iannucci Abhik Sen Paula Grammas |
| author_sort | Jaclyn Iannucci |
| collection | DOAJ |
| description | Mutations to the cholesterol transport protein apolipoprotein E (ApoE) have been identified as a major risk factor for the development of sporadic or late-onset Alzheimer’s disease (AD), with the <i>e4</i> allele representing an increased risk and the rare <i>e2</i> allele having a reduced risk compared to the primary <i>e3</i> form. The reasons behind the change in risk are not entirely understood, though ApoE4 has been connected to inflammation and toxicity in both the brain and the periphery. The goal of this study was to better understand how the ApoE isoforms (ApoE2/3/4) confer differential AD-related risk by assessing cell-specific ApoE-related neuroinflammatory and neurotoxic effects. We compared the effects of ApoE isoforms in vitro on human astrocytes, a human immortalized microglia cell line (HMC3), and the human neuroblastoma cell line SH-SY5Y. Cells were treated for 24 h with or without recombinant ApoE2, ApoE3, or ApoE4 (20 nM) and inflammation and toxicity markers assessed. Our results indicated the expression of inflammatory cytokines IL-1β, TNFα, and IL-6 in human astrocytes was increased in response to all ApoE isoforms, with ApoE4 evoking the highest level of cytokine expression. In response to ApoE2 or ApoE3, microglial cells showed reduced levels of microglial activation markers TREM2 and Clec7a, while ApoE4 induced increased levels of both markers. ApoE2 promoted neuron survival through increased BDNF release from astrocytes. In addition, ApoE2 promoted, while ApoE4 reduced, neuronal viability. Overall, these results suggest that ApoE4 acts on cells in the brain to promote inflammation and neuronal injury and that the deleterious effects of ApoE4 on these cells may, in part, contribute to its role as a risk factor for AD. |
| first_indexed | 2024-03-10T08:13:21Z |
| format | Article |
| id | doaj.art-1a2823261b964972accd80c50d1493a8 |
| institution | Directory Open Access Journal |
| issn | 1467-3037 1467-3045 |
| language | English |
| last_indexed | 2024-03-10T08:13:21Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj.art-1a2823261b964972accd80c50d1493a82023-11-22T10:28:34ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452021-05-0143121522510.3390/cimb43010018Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In VitroJaclyn Iannucci0Abhik Sen1Paula Grammas2George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USAGeorge & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USAGeorge & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USAMutations to the cholesterol transport protein apolipoprotein E (ApoE) have been identified as a major risk factor for the development of sporadic or late-onset Alzheimer’s disease (AD), with the <i>e4</i> allele representing an increased risk and the rare <i>e2</i> allele having a reduced risk compared to the primary <i>e3</i> form. The reasons behind the change in risk are not entirely understood, though ApoE4 has been connected to inflammation and toxicity in both the brain and the periphery. The goal of this study was to better understand how the ApoE isoforms (ApoE2/3/4) confer differential AD-related risk by assessing cell-specific ApoE-related neuroinflammatory and neurotoxic effects. We compared the effects of ApoE isoforms in vitro on human astrocytes, a human immortalized microglia cell line (HMC3), and the human neuroblastoma cell line SH-SY5Y. Cells were treated for 24 h with or without recombinant ApoE2, ApoE3, or ApoE4 (20 nM) and inflammation and toxicity markers assessed. Our results indicated the expression of inflammatory cytokines IL-1β, TNFα, and IL-6 in human astrocytes was increased in response to all ApoE isoforms, with ApoE4 evoking the highest level of cytokine expression. In response to ApoE2 or ApoE3, microglial cells showed reduced levels of microglial activation markers TREM2 and Clec7a, while ApoE4 induced increased levels of both markers. ApoE2 promoted neuron survival through increased BDNF release from astrocytes. In addition, ApoE2 promoted, while ApoE4 reduced, neuronal viability. Overall, these results suggest that ApoE4 acts on cells in the brain to promote inflammation and neuronal injury and that the deleterious effects of ApoE4 on these cells may, in part, contribute to its role as a risk factor for AD.https://www.mdpi.com/1467-3045/43/1/18apolipoprotein EneuroinflammationtoxicityAlzheimer’s disease |
| spellingShingle | Jaclyn Iannucci Abhik Sen Paula Grammas Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro Current Issues in Molecular Biology apolipoprotein E neuroinflammation toxicity Alzheimer’s disease |
| title | Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro |
| title_full | Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro |
| title_fullStr | Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro |
| title_full_unstemmed | Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro |
| title_short | Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro |
| title_sort | isoform specific effects of apolipoprotein e on markers of inflammation and toxicity in brain glia and neuronal cells in vitro |
| topic | apolipoprotein E neuroinflammation toxicity Alzheimer’s disease |
| url | https://www.mdpi.com/1467-3045/43/1/18 |
| work_keys_str_mv | AT jaclyniannucci isoformspecificeffectsofapolipoproteineonmarkersofinflammationandtoxicityinbraingliaandneuronalcellsinvitro AT abhiksen isoformspecificeffectsofapolipoproteineonmarkersofinflammationandtoxicityinbraingliaandneuronalcellsinvitro AT paulagrammas isoformspecificeffectsofapolipoproteineonmarkersofinflammationandtoxicityinbraingliaandneuronalcellsinvitro |