1α,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients
Mathew T Mizwicki, Guanghao Liu, Milan Fiala, Larry Magpantay, James Sayre, Avi Siani, Michelle Mahanian, Rachel Weitzman, Eric Y Hayden, Mark J Rosenthal, Ilka Nemere, John Ringman, David B Teplow, Mathew T Mizwicki, Guanghao Liu, Milan Fiala, Larry Magpantay, James Sayre, Avi Siani, Michelle Mahanian, Rachel Weitzman, Eric Y Hayden, Mark J Rosenthal, Ilka Nemere, John Ringman, David B Teplow
Abstract
As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.
Figures
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Figure 4
Differential TLR mRNA expression in…
Figure 4
Differential TLR mRNA expression in the Group 1 and Group 2 AD PBMCs…
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Two profiles in the baseline…
Figure 5
Two profiles in the baseline transcription of inflammatory and autoimmune genes observed in…
Figure 6
Soluble Aβ upregulates the transcription…
Figure 6
Soluble Aβ upregulates the transcription of inflammatory and autoimmune genes more so in…
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RvD1 retunes the transcription of…
Figure 7
RvD1 retunes the transcription of inflammatory and autoimmune genes whose transcription was altered…
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1,25D3 retunes the transcription of…
Figure 8
1,25D3 retunes the transcription of inflammatory and autoimmune genes whose transcription was altered…
Figure 9
The cytokine IL1β inhibits the…
Figure 9
The cytokine IL1β inhibits the action of 1,25D3 and RvD1 on Aβ phagocytosis.…
Figure 10
RvD1 and 1,25D3 inhibit the…
Figure 10
RvD1 and 1,25D3 inhibit the secretion of inflammatory cytokines from PBMCs of a…
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- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adolescent
- Adult
- Alzheimer Disease / complications*
- Alzheimer Disease / pathology
- Amyloid beta-Peptides / metabolism*
- Amyloid beta-Peptides / pharmacology
- Apoptosis / drug effects
- Cells, Cultured
- Child
- Cytokines / genetics
- Cytokines / metabolism
- Docosahexaenoic Acids / metabolism*
- Dose-Response Relationship, Drug
- Enzyme Inhibitors / pharmacology
- Female
- Gene Expression Regulation / drug effects
- Humans
- Inflammation / etiology*
- Male
- Peptide Fragments / pharmacology
- Pertussis Toxin / pharmacology
- Phagocytosis / drug effects
- Phagocytosis / immunology*
- RNA, Messenger / metabolism
- Time Factors
- Vitamin D / analogs & derivatives*
- Vitamin D / metabolism
- Young Adult
- Amyloid beta-Peptides
- Cytokines
- Enzyme Inhibitors
- Peptide Fragments
- RNA, Messenger
- amyloid beta-protein (1-42)
- dihydroxy-vitamin D3
- resolvin D1
- Vitamin D
- Docosahexaenoic Acids
- Pertussis Toxin
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040018/bin/nihms575347f4.jpg)
Figure 5
Two profiles in the baseline…
Figure 5
Two profiles in the baseline transcription of inflammatory and autoimmune genes observed in…
Figure 6
Soluble Aβ upregulates the transcription…
Figure 6
Soluble Aβ upregulates the transcription of inflammatory and autoimmune genes more so in…
Figure 7
RvD1 retunes the transcription of…
Figure 7
RvD1 retunes the transcription of inflammatory and autoimmune genes whose transcription was altered…
Figure 8
1,25D3 retunes the transcription of…
Figure 8
1,25D3 retunes the transcription of inflammatory and autoimmune genes whose transcription was altered…
Figure 9
The cytokine IL1β inhibits the…
Figure 9
The cytokine IL1β inhibits the action of 1,25D3 and RvD1 on Aβ phagocytosis.…
Figure 10
RvD1 and 1,25D3 inhibit the…
Figure 10
RvD1 and 1,25D3 inhibit the secretion of inflammatory cytokines from PBMCs of a…
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040018/bin/nihms575347f5.jpg)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040018/bin/nihms575347f6.jpg)
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040018/bin/nihms575347f7.jpg)
![Figure 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040018/bin/nihms575347f8.jpg)
![Figure 9](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040018/bin/nihms575347f9.jpg)
![Figure 10](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040018/bin/nihms575347f10.jpg)
Source: PubMed