biostudies-literatureTayran HKaren Toffler Charitable TrustNIA NIH HHSNIAResearch Council of NorwayThe Thompson Family Foundation IncColumbia University Irving Medical Center100642https://www.ebi.ac.uk/biostudies/studies/S-EPMC11480862biostudies-literatureUnknown4(9)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. ClinicalCell genomicsABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling.PMC11480862U19 AG074879Min YFlaherty DMa YReyes-Dumeyer DKanekiyo TKizil CBhattarai PTeich AFWang NTosto GWang XIs OJurisch-Yaksi NVardarajan BNJeong IMayeux RCosacak MIStenersen JMNelson NReddy JSYang ZGunasekaran TITayran HKassara NDogru RMQiao MYilmaz EErtekin-Taner NfalseABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling.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. Clinical2024-01-01T00:00:00Z2024 Sep2026-06-01T07:07:15.652Z2025-04-04T00:35:00.625ZS-EPMC114808623921647510.1016/j.xgen.2024.100642