FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology,Aging Cell

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FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology
Aging Cell ( IF 8.0 ) Pub Date : 2021-07-11 , DOI: 10.1111/acel.13432
Shuqi Du _{1,

2} , Feng Jin _{1,

3} , Laure Maneix _{1,

4} , Manasee Gedam _{1,

5} , Yin Xu ₁ , Andre Catic _{1,

2,

4} , Meng C Wang _{1,

2,

3,

6,

7} , Hui Zheng _{1,

2,

6}

Affiliation

The rise of life expectancy of the human population is accompanied by the drastic increases of age-associated diseases, in particular Alzheimer's disease (AD), and underscores the need to understand how aging influences AD development. The Forkhead box O transcription factor 3 (FoxO3) is known to mediate aging and longevity downstream of insulin/insulin-like growth factor signaling across species. However, its function in the adult brain under physiological and pathological conditions is less understood. Here, we report a region and cell-type-specific regulation of FoxO3 in the central nervous system (CNS). We found that FoxO3 protein levels were reduced in the cortex, but not hippocampus, of aged mice. FoxO3 was responsive to insulin/AKT signaling in astrocytes, but not neurons. Using CNS Foxo3-deficient mice, we reveal that loss of FoxO3 led to cortical astrogliosis and altered lipid metabolism. This is associated with impaired metabolic homoeostasis and β-amyloid (Aβ) uptake in primary astrocyte cultures. These phenotypes can be reversed by expressing a constitutively active FOXO3 but not a FOXO3 mutant lacking the transactivation domain. Loss of FoxO3 in 5xFAD mice led to exacerbated Aβ pathology and synapse loss and altered local response of astrocytes and microglia in the vicinity of Aβ plaques. Astrocyte-specific overexpression of FOXO3 displayed opposite effects, suggesting that FoxO3 functions cell autonomously to mediate astrocyte activity and also interacts with microglia to address Aβ pathology. Our studies support a protective role of astroglial FoxO3 against brain aging and AD.

中文翻译：

皮质星形胶质细胞中的 FoxO3 缺陷导致脂质代谢受损和淀粉样蛋白病变加重

人口预期寿命的延长伴随着与年龄相关的疾病，特别是阿尔茨海默氏病 (AD) 的急剧增加，并强调了了解衰老如何影响 AD 发展的必要性。Forkhead box O 转录因子 3 (FoxO3) 已知可介导跨物种的胰岛素/类胰岛素生长因子信号下游的衰老和长寿。然而，其在生理和病理条件下在成人大脑中的功能知之甚少。在这里，我们报告了中枢神经系统 (CNS) 中 FoxO3 的区域和细胞类型特异性调节。我们发现 FoxO3 蛋白水平在老年小鼠的皮层而非海马体中降低。FoxO3 对星形胶质细胞中的胰岛素/AKT 信号有反应，但对神经元没有反应。使用 CNS Foxo3-缺陷小鼠，我们发现 FoxO3 的缺失导致皮质星形胶质细胞增生和脂质代谢改变。这与原代星形胶质细胞培养物中代谢稳态和 β-淀粉样蛋白 (Aβ) 摄取受损有关。这些表型可以通过表达组成型活性 FOXO3 而不是缺乏反式激活域的 FOXO3 突变体来逆转。5xFAD 小鼠中 FoxO3 的缺失导致 Aβ 病理学和突触缺失加剧，并改变了 Aβ 斑块附近星形胶质细胞和小胶质细胞的局部反应。FOXO3 的星形胶质细胞特异性过表达表现出相反的效果，表明 FoxO3 自主发挥细胞功能以介导星形胶质细胞活性，并与小胶质细胞相互作用以解决 Aβ 病理学问题。我们的研究支持星形胶质细胞 FoxO3 对大脑老化和 AD 的保护作用。

更新日期：2021-08-19

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