講演情報
[O13-5]ダウン症候群関連遺伝子によるアルツハイマー病モデルマウスにおけるアミロイドβ凝集と致死性の抑制効果
○石原 慶一1, 河下 映里1, 勝田 瑞生2, 斉藤 美知子3, 左合 治彦4, 山川 和弘5, 秋葉 聡1, 高田 和幸2 (1.京都薬科大学 病態生化学分野, 2.京都薬科大学 統合薬科学系, 3.京都薬科大学 バイオサイエンス研究センター, 4.国立成育医療研究センター 周産期・母性診療センター, 5.名古屋市立大学大学院医学研究科 脳神経科学研究所 神経発達症遺伝学分野)
Down syndrome (DS), which is caused by triplication of chromosome 21 (Hsa21), is the leading genetic risk factor for early-onset Alzheimer’s disease (AD) presenting the classic pathological features of the brain with AD. As the reason of early onset AD in DS, increased copy number of the amyloid precursor protein (APP) gene in Hsa21 are suggested. However, the high incidence of early-onset AD in DS people could not be explained by merely 1.5-fold increase in APP expression, and other Hsa21 genes therefore likely modulate the development of AD. To understand the genetic mechanisms underlying early-onset AD in DS, we tried to identify the DS gene(s) to modify the development of AD. In this study, we generated mouse models of AD in DS by crossing DS mouse models with partial trisomies to AD mouse model expressing mutated APP and mutated presenilin 1. Surprisingly, at 9 months of age, amyloid-β (Aβ) aggregates in the hippocampus and cerebral cortex decreased in DS-AD mouse model with approximately 70 trisomic Hsa21 genes. In contrast, no suppressive effects were observed in other DS-AD mouse models with a shorter extra copy of Hsa21 genes (approximately 30 genes), suggesting that the remaining 40 genes include a putative suppressor of Aβ aggregation. We also found that APP transgene-associated mortality was suppressed in both DS-AD mouse models. These results indicate that APP transgene-associated mortality is independent to the accumulation of Aβ aggregates. Here we found certain gene(s) in Hsa21 suppresses the Aβ accumulation and mutated APP-associated mortality.