PUBLICATION
ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling
- Authors
- Tayran, H., Yilmaz, E., Bhattarai, P., Min, Y., Wang, X., Ma, Y., Wang, N., Jeong, I., Nelson, N., Kassara, N., Cosacak, M.I., Dogru, R.M., Reyes-Dumeyer, D., Stenersen, J.M., Reddy, J.S., Qiao, M., Flaherty, D., Gunasekaran, T.I., Yang, Z., Jurisch-Yaksi, N., Teich, A.F., Kanekiyo, T., Tosto, G., Vardarajan, B.N., İş, Ö., Ertekin-Taner, N., Mayeux, R., Kizil, C.
- ID
- ZDB-PUB-240902-10
- Date
- 2024
- Source
- Cell genomics 4(9): 100642 (Journal)
- Registered Authors
- Bhattarai, Prabesh, Cosacak, Mehmet Ilyas, Jurisch-Yaksi, Nathalie, Kizil, Caghan, Yilmaz, Elanur
- Keywords
- none
- Datasets
- GEO:GSE244550
- MeSH Terms
-
- Brain-Derived Neurotrophic Factor*/genetics
- Brain-Derived Neurotrophic Factor*/metabolism
- Humans
- Signal Transduction*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Zebrafish*
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Neuropeptide Y*/genetics
- Neuropeptide Y*/metabolism
- Animals
- Receptors, Nerve Growth Factor/genetics
- Receptors, Nerve Growth Factor/metabolism
- Synapses/metabolism
- Synapses/pathology
- Alzheimer Disease*/genetics
- Alzheimer Disease*/metabolism
- Alzheimer Disease*/pathology
- Amyloid beta-Peptides/genetics
- Amyloid beta-Peptides/metabolism
- Neurons/metabolism
- Neurons/pathology
- PubMed
- 39216475 Full text @ Cell Genom
Citation
Tayran, H., Yilmaz, E., Bhattarai, P., Min, Y., Wang, X., Ma, Y., Wang, N., Jeong, I., Nelson, N., Kassara, N., Cosacak, M.I., Dogru, R.M., Reyes-Dumeyer, D., Stenersen, J.M., Reddy, J.S., Qiao, M., Flaherty, D., Gunasekaran, T.I., Yang, Z., Jurisch-Yaksi, N., Teich, A.F., Kanekiyo, T., Tosto, G., Vardarajan, B.N., İş, Ö., Ertekin-Taner, N., Mayeux, R., Kizil, C. (2024) ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling. Cell genomics. 4(9):100642.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping