乳铁蛋白(lactoferrin, Lf)是铁结合糖蛋白，其抗感染之外的潜在“生物药物”价值受到关注。我们发现外源Lf可改善阿尔茨海默病(AD)模型小鼠的神经病理及认知障碍。进一步制备特异性敲除星形胶质细胞Lf基因的小鼠，RNA-Seq分析及体内外的前期实验表明，Lf缺失导致星形胶质细胞内调控胆固醇代谢的转录因子SREBP2表达下降、胆固醇外流减少，神经元的增值、迁移、分化和成熟受限，小鼠表现出认知和情感行为障碍。据此推测星形胶质细胞源Lf可能通过调控SREBP2的表达，调节胆固醇代谢，进而影响神经元的发育和功能，最终影响小鼠的情感和认知行为。本项目拟在分子和细胞水平，研究Lf调控SREBP2的机制，明确其在维持细胞胆固醇稳态中的作用；在整体水平，利用Lf敲除/敲入与AD模型小鼠，深入研究星形胶质细胞源Lf在AD中的作用，为阐明AD及情感认知障碍疾患的发生发展机制及干预措施提供新思路。

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized with β-amyloid protein (Aβ) deposition and tau hyperphosphorylation in the brain. Aβ is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ-secretases, which increased production, insufficient degradation and clearance by enzyme triggers subsequent pathological events such as synaptic degeneration, oxidative stress, neuroinflammation, tau hyperphosphorylation and neuronal loss, eventually causes cognitive deficits. To date, inhibition of the generation of Aβ is one of the prime strategies of AD therapy. .Lactoferrin (Lf), an iron-binding protein and an inflammatory modulator, exhibits similar chelating features like desferrioxamine, also performs as a normoxic mimetic of hypoxia, capable of stabilizing HIF-1α. In the brain of AD patient and transgenic mouse, Lf is abundant in Aβ plaques and tau-containing neurofibrillary tangles. It is important to consider that Lf prevents some denatured/misfolded proteins from aggregating, and multifunctional antiprion activities have been identified. These properties make Lf a valuable therapeutic candidate against AD. What’s exciting is that human Lf considerably alleviates the neuronal pathologies and behavior deficits in both the animal models of AD and Parkinson’s disease in our recent studies. Nevertheless, the clinic function of exogenous Lf remains largely controversial, suggesting that elucidation of the molecular mechanism of Lf is necessary. Previous studies exerted that the expression of astrocytic Lf is clearly elevated in the lesions of neurodegenerative diseases, indicating that the astrocytic Lf may have an important role in the progress of neurodegenerative diseases. However, to the best of our knowledge, the functions of astrocytic Lf in neurodegenerative diseases remain unexplored. In this study, the astrocytic Lf was specifically ablated in C57BL/6 mice, and then the RNA-Seq analysis was performed. Based on our prior experimental data and the results from RNA-Seq analysis, we speculate that astrocytic Lf regulates the cholesterol homeostasis via targeting transcriptional factor Sterol regulatory element-binding protein 2 (SREBP2), which affects neuronal differentiation and functions, and eventually modulates the emotional and cognitive abilities of mice. Next, we will investigate the underlying mechanism of astrocytic Lf in the regulation of SREBP2 in the molecular and cellular levels, and verify that Lf plays a vital role in regulating cholesterol homeostasis, emotional capacity and cognitive ability. Moreover, the knockout or over-expression of Lf in astrocytes in AD transgenic mice will be respectively constructed to unveil the functions and mechanisms of Lf in AD pathology. This study will provide a novel mechanism for the occurrence and development of some emotional and cognitive function impediment as well as neurodegenerative diseases. Perhaps, the Lf may be recognized as a potential biomedicine that will gain great attentions.