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+/− knockout...

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Published in:	Cell genomics Vol. 4; no. 9; p. 100642
Main Authors:	Tayran, Hüseyin, Yilmaz, Elanur, Bhattarai, Prabesh, Min, Yuhao, Wang, Xue, Ma, Yiyi, Wang, Ni, Jeong, Inyoung, Nelson, Nastasia, Kassara, Nada, Cosacak, Mehmet Ilyas, Dogru, Ruya Merve, Reyes-Dumeyer, Dolly, Stenersen, Jakob Mørkved, Reddy, Joseph S., Qiao, Min, Flaherty, Delaney, Gunasekaran, Tamil Iniyan, Yang, Zikun, Jurisch-Yaksi, Nathalie, Teich, Andrew F., Kanekiyo, Takahisa, Tosto, Giuseppe, Vardarajan, Badri N., İş, Özkan, Ertekin-Taner, Nilüfer, Mayeux, Richard, Kizil, Caghan
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 11-09-2024 Elsevier
Subjects:	Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer Disease - pathology Amyloid beta-Peptides - genetics Amyloid beta-Peptides - metabolism Animals ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism Brain-Derived Neurotrophic Factor - genetics Brain-Derived Neurotrophic Factor - metabolism Humans Neurons - metabolism Neurons - pathology Neuropeptide Y - genetics Neuropeptide Y - metabolism Receptors, Nerve Growth Factor - genetics Receptors, Nerve Growth Factor - metabolism Signal Transduction Synapses - metabolism Synapses - pathology Zebrafish Zebrafish Proteins - genetics Zebrafish Proteins - metabolism
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Summary:	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. [Display omitted] •ABCA7 knockout in zebrafish mimics Alzheimer’s disease (AD) pathology•Loss of ABCA7 reduces neuropeptide Y (NPY) in zebrafish and humans•NPY and BDNF signaling axis is essential for maintaining synaptic integrity in AD•Zebrafish reveals ABCA7-dependent resilience mechanisms conserved in humans In this study, Tayran et al. investigate the role of ABCA7, certain genetic variants of which act as risk factors for Alzheimer’s disease (AD), using a zebrafish AD model. They demonstrate that ABCA7-dependent induction of neuropeptide Y (NPY) and BDNF signaling is crucial for maintaining key resilience processes including synaptic integrity and astroglial proliferation. The findings uncover a previously unidentified mechanism by which brain resilience is impaired in AD patients and identify potential therapeutic targets to mitigate AD pathology.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally Lead contact
ISSN:	2666-979X 2666-979X
DOI:	10.1016/j.xgen.2024.100642