Exploring the hidden roles of the Y chromosome in Alzheimer’s disease: A cutting-edge organoid study
Description: Background:
The Y chromosome is considered a “genetic wasteland” because of its low gene density. However, loss of the Y chromosome (LOY), the most common somatic mutation in men’s aging, was recently shown to exacerbate age-related diseases, including heart failure and cancer (Abdel-Hafiz, Nature 2023; Sano, Science 2022). Furthermore, LOY is prevalent in the microglia of patients with Alzheimer’s disease (AD) (Vermeulen, Genome Res 2022). In a preliminary postmortem study of AD brains, I found the inflammatory phenotype in microglia with LOY.
Microglia-driven neuroinflammation is a critical feature in AD. In this study, we will use “neuroimmune organoids,” developed by my host laboratory (Schafer, Cell 2023), to investigate neuroinflammation induced by microglial LOY. This method involves the xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived brain organoids with microglia into the mouse brains. It allows the long-term investigation of human-specific microglial pathology to overcome the limitations of conventional rodent microglial models, which lack orthologs for many AD risk genes.
The cause of LOY remains unclear; however, blood LOY has been proposed to link to genomic instability, a feature of cancer. A postmortem study showed enrichment of genomic instability in AD microglia (Huang, bioRxiv 2024), inspiring a potential association between microglial LOY and genomic instability.
Aims:
This study aims to elucidate how microglial LOY arises and contributes to neuroinflammation in patients with AD using neuroimmune organoids.
Central Hypotheses:
Microglial LOY caused by genome instability exacerbates neuroinflammation in AD.
Experimental System:
This study is the first to apply neuroimmune organoids to neurodegenerative disease research.
1. Analysis of microglia with LOY in postmortem AD brains using single-nucleus RNA-seq, RNA-FISH, and immunostaining
2. Establishment of iPSCs with LOY, differentiation of microglia, and assessment of their inflammatory phenotype with RNA-seq and secretome analysis
3. Generation of neuroimmune organoids by the xenotransplantation of human brain organoids involving microglia with LOY into mouse brains, analysis of inflammatory phenotypes using immunostaining and single-cell RNA-seq, and comparisons with postmortem AD brains
4. Identification of the Y chromosome genes responsible for the LOY phenotype using CRISPRi and RNA-seq
5. Development of Y chromosome reporter iPSCs and identification of cancer driver genes inducing LOY using CRISPR screening and fluorescence-activated cell sorting (FACS)
Conclusions:
This study is expected to redefine the role of the Y chromosome in the brain and to establish neuroimmune organoids as an ideal tool for studying microglial pathology in neurodegeneration. Moreover, it will challenge the notion that neurodegeneration and cancer arise from distinct mechanisms by investigating genomic instability as a cause of microglial LOY.
Funder: Human Frontier Science Program
Amount:
Funding type: award
Start date: 2026-04-01
End date: 2029-03-31
Investigator: Kotaro Oiwa
Institution: Nagoya University
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: LT0016/2025-L
OpenAlex ID: G2849947501