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Status |
Public on Jul 19, 2024 |
Title |
ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling |
Organism |
Danio rerio |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7+/- knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7-/- suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.
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Overall design |
WT and abca7+/- zebrafish injected with Amyloid-beta 42 peptide as described (Bhatatrai et al. 2016) and cells were dissociated, sorted by FACS as described (Cosacak et al. 2019). The single-cell encapsulation and cDNA synthesis done by following 10X Genomics' workflows. The reads were aligned to zebrafish genome (GRChZ 11, v 105) was used for gene annotation and assigning reads to genes. Cellranger software version 6.1.2 was used to process the data
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Contributor(s) |
Yilmaz E, Tayran H, Cosacak MI, Bhattarai P, Kizil C |
Citation(s) |
39216475 |
NIH grant(s) |
Grant ID |
Grant title |
Affiliation |
Name |
R01 AG067501 |
Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious Order |
Trustees of Columbia University in the City of New York |
Richard P Mayeux |
U24 AG056270 |
National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS) |
Trustees of Columbia University in the City of New York |
Richard P Mayeux |
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Submission date |
Oct 03, 2023 |
Last update date |
Oct 18, 2024 |
Contact name |
Caghan Kizil |
E-mail(s) |
ck2893@cumc.columbia.edu
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Organization name |
Columbia University
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Department |
Neurology & TAUB Institute
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Street address |
650 W 168 St BB1212
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City |
New York |
ZIP/Postal code |
10032 |
Country |
USA |
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Platforms (1) |
GPL20828 |
Illumina NextSeq 500 (Danio rerio) |
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Samples (4)
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GSM7819018 |
telencephalon, abca7 k/o - Ab42 injected |
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Relations |
BioProject |
PRJNA1023540 |
Supplementary file |
Size |
Download |
File type/resource |
GSE244550_RAW.tar |
226.6 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
Raw data are available in SRA |
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