Journal Article

DZNE-2024-01131

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling.

Tayran, H. ; Yilmaz, E. ; Bhattarai, P.Extern* ; Min, Y. ; Wang, X. ; Ma, Y. ; Wang, N. ; Jeong, I. ; Nelson, N. ; Kassara, N. ; Cosacak, M. I.DZNE* ; Dogru, R. M. ; Reyes-Dumeyer, D. ; Stenersen, J. M. ; Reddy, J. S. ; Qiao, M. ; Flaherty, D. ; Gunasekaran, T. I. ; Yang, Z. ; Jurisch-Yaksi, N. ; Teich, A. F. ; Kanekiyo, T. ; Tosto, G. ; Vardarajan, B. N. ; İş, Ö. ; Ertekin-Taner, N. ; Mayeux, R. ; Kizil, C.

2024
Elsevier Amsterdam

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Please use a persistent id in citations: 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.

Keyword(s): Brain-Derived Neurotrophic Factor: metabolism (MeSH) ; Brain-Derived Neurotrophic Factor: genetics (MeSH) ; Animals (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Neuropeptide Y: metabolism (MeSH) ; Neuropeptide Y: genetics (MeSH) ; Humans (MeSH) ; Zebrafish (MeSH) ; Signal Transduction (MeSH) ; Synapses: metabolism (MeSH) ; Synapses: pathology (MeSH) ; ATP-Binding Cassette Transporters: genetics (MeSH) ; ATP-Binding Cassette Transporters: metabolism (MeSH) ; Receptors, Nerve Growth Factor: genetics (MeSH) ; Receptors, Nerve Growth Factor: metabolism (MeSH) ; Zebrafish Proteins: genetics (MeSH) ; Zebrafish Proteins: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Peptides: genetics (MeSH) ; Brain-Derived Neurotrophic Factor ; Neuropeptide Y ; ATP-Binding Cassette Transporters ; Receptors, Nerve Growth Factor ; Zebrafish Proteins ; Amyloid beta-Peptides

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Contributing Institute(s):

1. Mechanisms of Induced Plasticity of the Vertebrate Brain (AG Kizil)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; ; ; ; Article Processing Charges ; DOAJ Seal ; Fees ; PubMed Central ; SCOPUS

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