脑源性乳铁蛋白通过清除和降解β-淀粉样蛋白延缓脑衰老及阿尔茨海默病退行性变的分子网络机制

近期研究表明乳铁蛋白(Lf)可作为脑衰老以及散发性阿尔茨海默病 (AD) 的生物标志物，脑源性Lf是抑制β-淀粉样蛋白 (Aβ) 脑内沉积，改善脑老化和认知能力的潜在干预靶标和生物活性分子，但其机制不清。我们前期发现外源性Lf通过激活APP非淀粉样剪切途径显著抑制AD小鼠脑内Aβ产生与沉积；Lf通过上调水通道蛋白AQP4激活胶质淋巴系统促进Aβ转运至外周循环被清除出脑。据此我们推测：Lf通过调控星形胶质细胞p38/AQP4信号途径，促进Aβ清除；通过调控神经元LRP1和转录因子HIF-1α促进Aβ内化降解并抑制Aβ生成；并通过竞争铁离子阻止“Aβ瀑布”下游事件乃至神经元铁死亡的发生。为此，本项目应用星形胶质细胞和神经元过表达Lf的转基因小鼠并将其与APP/PS1小鼠杂交，深度挖掘脑源性Lf抑制Aβ沉积和铁死亡的分子机制，为将Lf作为干预脑衰老及其向退行性变化的生物活性分子提供科学依据。

Recent studies have shown that lactoferrin (LF) is a potential biomarker of aging brain and sporadic Alzheimer's disease (AD). Brain-derived Lf is an effective intervention target and bioactive molecule to inhibit the deposition of β-amyloid protein (Aβ) in brain and improve brain aging and cognitive ability. However, the concrete mechanism remains unknown. It has been reported that LF can significantly inhibit the production and deposition of Aβ in the brain of AD mice by activating non-amyloidogenesis pathway of β-amyloid precursor protein (APP). In this project we found that LF can activate glymphatic system by up regulating AQP4, and promote Aβ transport to peripheral circulation to be cleared out of brain. Therefore, we speculate that LF promotes Aβ clearance by regulating p38/AQP4 signaling pathway in astrocytes; promotes Aβ internalization degradation and inhibits Aβ production by regulating neuronal LRP1 and HIF-1α; and prevents the downstream events of "Aβ cascade " and even neuronal ferroptosis by competing for iron ions. Therefore, in this project, we used transgenic mice with overexpression of LF in astrocytes and neurons and hybridized them with APP/PS1 mice to deeply explore the mechanism of brain-derived LF inhibiting Aβ production and deposition and neuronal ferroptosis, so as to provide an important scientific basis for the use of Lf as an effective intervention target and bioactive molecule for brain aging and its transformation to neurodegenerative diseases.