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| Status |
Public on Jun 05, 2024 |
| Title |
Arachidonic acid mobilization and peroxidation promote microglial dysfunction in Aβ pathology |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aβ pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted Lysophosphatidylcholine Acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing phospholipids, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in the AppNL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aβ plaques and promoting the compaction of Aβ deposits. Mechanistically, sc-RNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression.
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| Overall design |
To manipulate ARA-containing PLs in microglia, we genetically deleted Lysophosphatidylcholine Acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. We analyzed the impact of Lpcat3 deletion on microgllia response to Aβ pathology using immunostaining, bulk and single-cell RNA seq, and flow cytometry.
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| Contributor(s) |
Lin D, Gao J |
| Citation(s) |
38866484 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AG073310 |
Targeting IDOL-ApoE receptor pathway in Alzheimer's disease |
OHIO STATE UNIVERSITY |
Jie Gao |
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| Submission date |
May 31, 2024 |
| Last update date |
Sep 04, 2024 |
| Contact name |
Jie Gao |
| E-mail(s) |
Jie.Gao@osumc.edu
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| Organization name |
The Ohio State University
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| Department |
The Department of Neuroscience
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| Lab |
Gao Lab
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| Street address |
460 W. 12th Ave
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| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43210 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (13)
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| GSM8301015 |
Hippocampus from AppNL-G-F; Lpcat3 f/f; vav1-CRE, 9 mo; 3283 |
| GSM8301016 |
Hippocampus from AppNL-G-F; Lpcat3 f/f; vav1-CRE, 9 mo; 3284 |
| GSM8301017 |
Hippocampus from AppNL-G-F; Lpcat3 f/f; vav1-CRE, 9 mo; 3285 |
| GSM8301018 |
Hippocampus from AppNL-G-F; Lpcat3 f/f; vav1-CRE, 9 mo; 3286 |
| GSM8301019 |
Hippocampus from AppNL-G-F; Lpcat3 f/f, 9 mo; 3287 |
| GSM8301020 |
Hippocampus from AppNL-G-F; Lpcat3 f/f; vav1-CRE, 9 mo; 3288 |
| GSM8301021 |
Hippocampus from AppNL-G-F; Lpcat3 f/f, 9 mo; 3296 |
| GSM8301022 |
Hippocampus from AppNL-G-F; Lpcat3 f/f, 9 mo; 3297 |
| GSM8301023 |
Hippocampus from AppNL-G-F; Lpcat3 f/f, 9 mo; 3298 |
| GSM8301024 |
Hippocampus from AppNL-G-F; Lpcat3 f/f; vav1-CRE, 9 mo; 3300 |
| GSM8301025 |
Hippocampus from AppNL-G-F; Lpcat3 f/f; vav1-CRE, 9 mo; 4301 |
| GSM8301026 |
Hippocampus from AppNL-G-F; Lpcat3 f/f, 9 mo; 4306 |
| GSM8301027 |
Hippocampus from AppNL-G-F; Lpcat3 f/f, 9 mo; 4307 |
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| Relations |
| BioProject |
PRJNA1118825 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE268838_ProcessedData_CountMatrix.txt.gz |
940.3 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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