Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
Brain Repair Centre, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
Sci Rep. 2023 Feb 4;13(1):2043. doi: 10.1038/s41598-023-29248-x.
Reduced insulin-like growth factor 2 (IGF2) levels in Alzheimer's disease (AD) may be the mechanism relating age-related metabolic disorders to dementia. Since Igf2 is an imprinted gene, we examined age and sex differences in the relationship between amyloid-beta 1-42 (Aβ) accumulation and epigenetic regulation of the Igf2/H19 gene cluster in cerebrum, liver, and plasma of young and old male and female 5xFAD mice, in frontal cortex of male and female AD and non-AD patients, and in HEK293 cell cultures. We show IGF2 levels, Igf2 expression, histone acetylation, and H19 ICR methylation are lower in females than males. However, elevated Aβ levels are associated with Aβ binding to Igf2 DMR2, increased DNA and histone methylation, and a reduction in Igf2 expression and IGF2 levels in 5xFAD mice and AD patients, independent of H19 ICR methylation. Cell culture results confirmed the binding of Aβ to Igf2 DMR2 increased DNA and histone methylation, and reduced Igf2 expression. These results indicate an age- and sex-related causal relationship among Aβ levels, epigenomic state, and Igf2 expression in AD and provide a potential mechanism for Igf2 regulation in normal and pathological conditions, suggesting IGF2 levels may be a useful diagnostic biomarker for Aβ targeted AD therapies.
阿尔茨海默病（AD）中胰岛素样生长因子 2（IGF2）水平降低可能是将与年龄相关的代谢紊乱与痴呆联系起来的机制。由于 Igf2 是一个印迹基因，我们研究了在年轻和老年雄性和雌性 5xFAD 小鼠的大脑、肝脏和血浆中，淀粉样蛋白-β 1-42（Aβ）积累与 Igf2/H19 基因簇的表观遗传调控之间的关系，以及在男性和女性 AD 和非 AD 患者的额皮质中，以及在 HEK293 细胞培养物中，年龄和性别差异。我们发现 IGF2 水平、Igf2 表达、组蛋白乙酰化和 H19 ICR 甲基化在雌性中低于雄性。然而，升高的 Aβ 水平与 Aβ 与 Igf2 DMR2 结合有关，导致 DNA 和组蛋白甲基化增加，以及 Igf2 表达和 IGF2 水平降低，在 5xFAD 小鼠和 AD 患者中，与 H19 ICR 甲基化无关。细胞培养结果证实了 Aβ 与 Igf2 DMR2 的结合增加了 DNA 和组蛋白甲基化，并降低了 Igf2 表达。这些结果表明，在 AD 中，Aβ 水平、表观基因组状态和 Igf2 表达之间存在与年龄和性别相关的因果关系，并为 Igf2 在正常和病理条件下的调节提供了潜在的机制，表明 IGF2 水平可能是 Aβ 靶向 AD 治疗的有用诊断生物标志物。
