言語種別	英語
発表タイトル	Revealing the pathogenesis of ALSP/HDLS using Human Induced Pluripotent Stem Cell-Derived Microglia
会議名	第66回日本神経学会学術大会
学会区分	全国規模の学会
発表形式	口頭
講演区分	一般
発表者・共同発表者	◎藤田理奈, 濱谷美緒, 木村公俊, 粟屋智就, 吉冨啓之, 和泉唯信, 柿田明美, 越智博文, 近藤誉之, 松本理器, 高橋良輔, 井上治久, 他田真理, 上野英樹
発表年月日	2025/05/21
開催地 （都市, 国名）	大阪
開催期間	2025/05/21～2025/05/24
概要	[Introduction]Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is known as a primary microgliopathy caused by pathogenic CSF1R gene mutations. We aim to clarify how mutant CSF1R impacts microglial phenotype and contributes to the pathology of ALSP. [Methods]Microglia-like cells (MGLs) were generated from induced pluripotent stem cells (iPSCs) of 5 healthy controls (HC) and 3 ALSP patients and phenotypic analysis was performed. [Results]The transcriptomic analysis revealed alterations in intracellular metabolism-related genes in MGLs derived from ALSP (ALSP-MGLs). Using an extracellular flux analyzer, we found that the proportion of mitochondrial respiration in ATP production was increased in ALSP-MGLs. Additionally, we observed mitochondrial damage and an increase in mitochondrial reactive oxygen species (ROS)/oxidative stress in ALSP-MGLs, known as a hallmark of cellular senescence. ALSP-MGLs expressed other senescence makers such as γH2AX and increased pro-inflammatory secretary phenotype. Co-culture of ALSP-MGLs induced apoptotic marker caspase-3 activation in neurons, which was abrogated by adding ROS scavenger glutathione in the coculture medium. [Conclusions]CSF1R signaling dysfunction causes metabolic alteration and promotes senescent phenotype in microglia, leading to the increase of ROS production, which results in neuronal loss in ALSP brain.