Tyler Sakamoto

All Publications

• Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice CELL REPORTS Fukui, M., Kaise, T., Masaki, T., Sakamoto, T., Kageyama, R. 2026; 45 (4): 117250

  Abstract

  Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously showed that inducing Plagl2 and antagonizing Dyrk1a (iPaD) rejuvenates aged neural stem cells (NSCs), enhancing neurogenesis and cognition in aged mice. Here, we found that NSC-specific iPaD treatment activates neurogenesis, reduces amyloid-β deposition, and improves cognition in Alzheimer's disease model mice. Transcriptomic analysis revealed widespread changes in gene expression in the hippocampus after iPaD treatment. The upregulated genes include those associated with astrocyte and microglial activation involved in amyloid-β clearance, while several genes upregulated in Alzheimer's disease are downregulated. Among the latter genes, knockdown of Prkag2 in the hippocampus most effectively enhances neurogenesis and reduces amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activate AMP-activated protein kinase signaling, upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.

  View details for DOI 10.1016/j.celrep.2026.117250

  View details for Web of Science ID 001742653400001

  View details for PubMedID 41964958

• In vivo transplantation of mammalian vascular organoids onto the chick chorioallantoic membrane reveals the formation of a hierarchical vascular network. Scientific reports Kowalski, W. J., Vatti, S., Sakamoto, T., Li, W., Odutola, S. R., Liu, C., Chen, G., Boehm, M., Mukouyama, Y. S. 2025; 15 (1): 7150

  Abstract

  The dynamic remodeling of the nascent vascular network into a mature hierarchy is essential for embryo survival. Cell behaviors and signaling mechanisms are often investigated with animal models and perfused microchannels, giving insights into this process. To support these studies and enrich our understanding, we demonstrate a complementary approach using vascular organoids. Organoids initially form a primitive endothelial plexus lined with NG2+/PDGFRβ+ mural cell progenitors containing immature pericytes, but there is no formation of large-diameter vessels covered with αSMA+ cells containing immature vascular smooth muscle cells (vSMCs). After transplantation to the chick chorioallantoic membrane, the network reorganizes into a branched architecture with large-diameter vessels covered by αSMA+ cells. We additionally show that blood flow from the host circulation perfuses the organoid. Compared with the developing skin vasculature in mouse embryos, organoids successfully recapitulate vascular morphogenesis, both in vitro and after transplantation. The model described here presents a further approach to enhance the study of vascular remodeling.

  View details for DOI 10.1038/s41598-025-91826-y

  View details for PubMedID 40021912

  View details for PubMedCentralID PMC11871353

• Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders. Human genetics Andersen, R. E., Alkuraya, I. F., Ajeesh, A., Sakamoto, T., Mena, E. L., Amr, S. S., Romi, H., Kenna, M. A., Robson, C. D., Wilch, E. S., Nalbandian, K., Piña-Aguilar, R., Walsh, C. A., Morton, C. C. 2024; 143 (7): 921-938

  Abstract

  In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions.

  View details for DOI 10.1007/s00439-024-02693-y

  View details for PubMedID 39060644

  View details for PubMedCentralID PMC11294402