2. Academic Validation
  3. ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling

ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling

  • Cell Genom. 2024 Sep 11;4(9):100642. doi: 10.1016/j.xgen.2024.100642.
Hüseyin Tayran 1,  Elanur Yilmaz 1,  Prabesh Bhattarai 1,  Yuhao Min 2,  Xue Wang 3,  Yiyi Ma 4,  Ni Wang 2,  Inyoung Jeong 5,  Nastasia Nelson 1,  Nada Kassara 6,  Mehmet Ilyas Cosacak 7,  Ruya Merve Dogru 6,  Dolly Reyes-Dumeyer 8,  Jakob Mørkved Stenersen 5,  Joseph S Reddy 2,  Min Qiao 8,  Delaney Flaherty 9,  Tamil Iniyan Gunasekaran 8,  Zikun Yang 8,  Nathalie Jurisch-Yaksi 5,  Andrew F Teich 10,  Takahisa Kanekiyo 11,  Giuseppe Tosto 8,  Badri N Vardarajan 8,  Özkan İş 2,  Nilüfer Ertekin-Taner 12,  Richard Mayeux 13,  Caghan Kizil 14
Affiliations

Affiliations

  • 1 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA.
  • 2 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
  • 3 Department of Quantitative Health Sciences, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
  • 4 Department of Neurology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA.
  • 5 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 6 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA.
  • 7 German Center for Neurodegenerative Diseases (DZNE), Tatzberg 41, 01307 Dresden, Germany.
  • 8 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
  • 9 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA.
  • 10 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA.
  • 11 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA; Center for Regenerative Biotherapeutics, Mayo Clinic, Jacksonville, FL 32224, USA.
  • 12 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
  • 13 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University, 630 West 168th Street, New York, NY 10032, USA; Department of Psychiatry, College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, Columbia University, 722 W. 168th St., New York, NY 10032, USA.
  • 14 The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University, 630 West 168th Street, New York, NY 10032, USA. Electronic address: ck2893@cumc.columbia.edu.
PMID: 39216475 DOI: 10.1016/j.xgen.2024.100642
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.

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