TY  - JOUR
AU  - Tayran, Hüseyin
AU  - Yilmaz, Elanur
AU  - Bhattarai, Prabesh
AU  - Min, Yuhao
AU  - Wang, Xue
AU  - Ma, Yiyi
AU  - Wang, Ni
AU  - Jeong, Inyoung
AU  - Nelson, Nastasia
AU  - Kassara, Nada
AU  - Cosacak, Mehmet Ilyas
AU  - Dogru, Ruya Merve
AU  - Reyes-Dumeyer, Dolly
AU  - Stenersen, Jakob Mørkved
AU  - Reddy, Joseph S
AU  - Qiao, Min
AU  - Flaherty, Delaney
AU  - Gunasekaran, Tamil Iniyan
AU  - Yang, Zikun
AU  - Jurisch-Yaksi, Nathalie
AU  - Teich, Andrew F
AU  - Kanekiyo, Takahisa
AU  - Tosto, Giuseppe
AU  - Vardarajan, Badri N
AU  - İş, Özkan
AU  - Ertekin-Taner, Nilüfer
AU  - Mayeux, Richard
AU  - Kizil, Caghan
TI  - ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling.
JO  - Cell genomics
VL  - 4
IS  - 9
SN  - 2666-979X
CY  - Amsterdam
PB  - Elsevier
M1  - DZNE-2024-01131
SP  - 100642
PY  - 2024
AB  - 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.
KW  - Brain-Derived Neurotrophic Factor: metabolism
KW  - Brain-Derived Neurotrophic Factor: genetics
KW  - Animals
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: pathology
KW  - Neuropeptide Y: metabolism
KW  - Neuropeptide Y: genetics
KW  - Humans
KW  - Zebrafish
KW  - Signal Transduction
KW  - Synapses: metabolism
KW  - Synapses: pathology
KW  - ATP-Binding Cassette Transporters: genetics
KW  - ATP-Binding Cassette Transporters: metabolism
KW  - Receptors, Nerve Growth Factor: genetics
KW  - Receptors, Nerve Growth Factor: metabolism
KW  - Zebrafish Proteins: genetics
KW  - Zebrafish Proteins: metabolism
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Peptides: genetics
KW  - Brain-Derived Neurotrophic Factor (NLM Chemicals)
KW  - Neuropeptide Y (NLM Chemicals)
KW  - ATP-Binding Cassette Transporters (NLM Chemicals)
KW  - Receptors, Nerve Growth Factor (NLM Chemicals)
KW  - Zebrafish Proteins (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11480862
C6  - pmid:39216475
DO  - DOI:10.1016/j.xgen.2024.100642
UR  - https://pub.dzne.de/record/272136
ER  -