Honda Keiko, Saito Yuhki, Saito Haruka, Toyoda Megumi, Abe Ruriko, Saito Takashi, Saido Takaomi C, Michikawa Makoto, Taru Hidenori, Sobu Yuriko, Hata Saori, Nakaya Tadashi, Suzuki Toshiharu
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Laboratory of Molecular Neuro-Oncology, The Rockefeller University, NY, USA.
Neurobiol Aging. 2023 Mar;123:63-74. doi: 10.1016/j.neurobiolaging.2022.12.003. Epub 2022 Dec 17.
Apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease (AD). Here, we investigated brain amyloid-β (Aβ) accumulation throughout the aging process in an amyloid precursor protein (APP) knock-in (KI) mouse model of AD that expresses human APP with or without human apoE4 or apoE3. Brain Aβ42 levels were significantly lower in 9-month-old mice that express human isoforms of apoE than in age-matched APP-KI control mice. Linear accumulation of Aβ42 began in 5-month-old apoE4 mice, and a strong increase in Aβ42 levels was observed in 21-month-old apoE3 mice. Aβ42 levels in cerebroventricular fluid were higher in apoE3 than in apoE4 mice at 6-7 months of age, suggesting that apoE3 is more efficient at clearing Aβ42 than apoE4 at these ages. However, apoE3 protein levels were lower than apoE4 protein levels in the brains of 21-month-old apoE3 and apoE4 mice, respectively, which may explain the rapid increase in brain Aβ42 burden in apoE3 mice. We identified genes that were downregulated in a human apoE-dependent (apoE4 > apoE3) and age-dependent (apoE3 = apoE4) manner, which may regulate brain Aβ burden and/or AD progression. Analysis of gene expression in AD mouse models helps identify molecular mechanisms of pleiotropy by the human APOE gene during aging.
载脂蛋白E4（apoE4）是阿尔茨海默病（AD）的一个风险因素。在此，我们在一个表达人淀粉样前体蛋白（APP）且带有或不带有人类apoE4或apoE3的AD淀粉样前体蛋白（APP）基因敲入（KI）小鼠模型中，研究了整个衰老过程中脑内淀粉样β蛋白（Aβ）的积累情况。表达人类apoE异构体的9月龄小鼠的脑Aβ42水平显著低于年龄匹配的APP-KI对照小鼠。Aβ42在5月龄的apoE4小鼠中开始呈线性积累，并且在21月龄的apoE3小鼠中观察到Aβ42水平大幅升高。在6 - 7月龄时，apoE3小鼠脑脊液中的Aβ42水平高于apoE4小鼠，这表明在这些年龄段，apoE3比apoE4更有效地清除Aβ42。然而，在21月龄的apoE3和apoE4小鼠脑中，apoE3蛋白水平分别低于apoE4蛋白水平，这可能解释了apoE3小鼠脑内Aβ42负担的快速增加。我们鉴定了以人类apoE依赖（apoE4 > apoE3）和年龄依赖（apoE3 = apoE4）方式下调的基因，这些基因可能调节脑Aβ负担和/或AD进展。对AD小鼠模型中基因表达的分析有助于确定衰老过程中人类APOE基因多效性的分子机制。
