| First Author | Dorey E | Year | 2017 |
| Journal | J Alzheimers Dis | Volume | 57 |
| Issue | 4 | Pages | 1265-1279 |
| PubMed ID | 28372324 | Mgi Jnum | J:378941 |
| Mgi Id | MGI:8286400 | Doi | 10.3233/JAD-160133 |
| Citation | Dorey E, et al. (2017) Apolipoprotein E Isoforms Differentially Regulate Alzheimer's Disease and Amyloid-beta-Induced Inflammatory Response in vivo and in vitro. J Alzheimers Dis 57(4):1265-1279 |
| abstractText | Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Abeta-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Abeta42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Abeta42 and/or vitamin D receptor (VDR) agonist, 1alpha,25-dihydroxyvitamin D3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, Abeta ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by Abeta42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against Abeta42-induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against Abeta42-induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in Abeta42-treated astrocytes. Application of 1alpha,25-dihydroxyvitamin D3 completely inhibited Abeta-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/Abeta-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration. |
