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| Status |
Public on Jun 10, 2024 |
| Title |
Alzheimer’s Disease Protective Allele of CLU Promotes Neuron Excitability, Neuron-glia Lipid Transfer and Astrocytic Lipid Droplets via neuronal CLU |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Disease causal mechanism remains largely unknown for most Alzheimer’s disease (AD) genome-wide association studies (GWAS) risk loci, including the Clusterin (CLU) locus. Here, leveraging our approach to identify functional GWAS risk variants that show allele-specific open chromatin (ASoC), we nominated a putative AD causal SNP rs1532278 (T/C) of CLU that showed strong ASoC specifically in iPSC-derived excitatory neurons (iGlut). We found the AD protective allele T of rs1532278 elevated neuronal CLU and promoted neuron excitability. Transcriptomic analysis of iGlut (T/T vs. C/C) co-cultured with mouse astrocytes surprisingly showed allele T upregulated lipid synthesis and astrocytic lipid metabolism pathways. Further corroborative functional studies mechanistically tied allele T to CLU-facilitated neuron-glia lipid transfer and astrocytic lipid droplet (LD) formation. Interestingly, astrocytes with more LD were found to uptake less glutamate likely due to reactive oxygen species (ROS), which may contribute to CLU-promoted neuron excitability. Our study uncovered a previously unappreciated protective role of neuronal CLU in maintaining proper neuronal excitability through lipid-mediated neuron-glia communication.
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| Overall design |
We co-cultured CRISPR-cas 9 engneered and iPS-derived glutamatergic neurons and primary mouse astrocytes to investigate SNP rs1532278 dominated interactive effect between these two cell types.
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| Contributor(s) |
Duan J, Zhao X, Li Y, Zhang S |
| Citation(s) |
39185522 |
| |
| Submission date |
Jun 05, 2024 |
| Last update date |
Sep 27, 2024 |
| Contact name |
Jubao Duan |
| E-mail(s) |
jduan69@gmail.com
|
| Phone |
(224) 364-7564
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| Organization name |
NorthShore University HealthSystem
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| Department |
Center for Psychiatric Genetics
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| Lab |
Unit of Functional Genomics in Psychiatry
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| Street address |
1001 University Place
|
| City |
Evanston |
| State/province |
IL |
| ZIP/Postal code |
60201 |
| Country |
USA |
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| Platforms (1) |
| GPL16512 |
Illumina HiSeq 2000 (Homo sapiens; Mus musculus) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA1120422 |
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