ABCA7-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<sup>+/-</sup> 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<sup>-/-</sup> 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.
Authors
- Nastasia Nelson
- Giuseppe Tosto (ORCID: https://orcid.org/0000-0001-7075-8245)
- Nathalie Jurisch‐Yaksi (ORCID: https://orcid.org/0000-0002-8767-6120)
- Joseph S. Reddy (ORCID: https://orcid.org/0000-0002-1783-4453)
- Tamil Iniyan Gunasekaran (ORCID: https://orcid.org/0000-0002-8639-5060)
- Mehmet İlyas Coşacak (ORCID: https://orcid.org/0000-0003-2978-3902)
- Takahisa Kanekiyo (ORCID: https://orcid.org/0000-0001-6751-9374)
- Inyoung Jeong (ORCID: https://orcid.org/0000-0003-3554-3032)
- Özkan İş (ORCID: https://orcid.org/0000-0003-4070-6756)
- Yuhao Min (ORCID: https://orcid.org/0000-0001-8775-8743)
- Hüseyin Tayran
- Zikun Yang (ORCID: https://orcid.org/0000-0002-8834-6377)
- Çağhan Kızıl (ORCID: https://orcid.org/0000-0002-8164-9762)
- Andrew F. Teich (ORCID: https://orcid.org/0000-0002-1916-8490)
- Elanur Yılmaz (ORCID: https://orcid.org/0000-0001-7045-5068)
- Nilüfer Ertekin‐Taner (ORCID: https://orcid.org/0000-0003-4436-8889)
- Richard P Mayeux (ORCID: https://orcid.org/0000-0001-6519-9696)
- Prabesh Bhattarai (ORCID: https://orcid.org/0000-0003-2991-5514)
- Badri Narayan Vardarajan (ORCID: https://orcid.org/0000-0002-5560-4085)
- Dolly Reyes‐Dumeyer (ORCID: https://orcid.org/0000-0003-3572-8248)
- Rüya Merve Dogru
- Nada Kassara
- Xue Wang (ORCID: https://orcid.org/0000-0003-1964-4124)
- Ni Wang (ORCID: https://orcid.org/0000-0002-1796-7803)
- Min Qiao (ORCID: https://orcid.org/0000-0002-5823-4892)
- Yiyi Ma (ORCID: https://orcid.org/0000-0002-3609-8877)
- Jakob Mørkved Stenersen
- Delaney Flaherty
Institutions
- Norwegian University of Science and Technology (NO)
- Columbia University Irving Medical Center (US)
- German Center for Neurodegenerative Diseases (DE)
- Jacksonville College (US)
- Mayo Clinic in Florida (US)
- Columbia University (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1016/j.xgen.2024.100642
- Citations
- 14
- Primary Topic
- Nuclear Receptors and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- Alzheimer's Association
- Mayo Foundation for Medical Education and Research
- Arizona Department of Health Services
- CurePSP
- Rush University
- Thompson Family Foundation
- Karen Toffler Charitable Trust
- Norges Forskningsråd
- Arizona Biomedical Research Commission
- National Institutes of Health
- Irving Medical Center, Columbia University
- National Institute on Aging
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences