Nature：AAV载体介导脑啡肽基因可改善AD实验小鼠认知功能减退

　　脑内β淀粉样蛋白(Aβ)的蓄积与阿尔兹海默氏病（AD）的认知功能减退有紧密联系，通过立体定位输注，向AD实验小鼠海马内输注脑啡肽编码病毒载体，可检测出实验小鼠脑内Aβ含量的降低。但处理AD患者脑内广泛分布的Aβ需要更有效和广泛的递送。

　　近期《科学报告》（Scientific Reports）网络版刊发的一篇研究的结果显示，当必须进行脑内治疗基因整体转导时，腺联病毒（adeno-associated virus，AAV）载体介导基因转移或可以为神经退行性疾病的治疗提供一个治疗策略。研究者设计了一种AAV载体，在实验小鼠身上，其经外周给药后可提供贯穿全脑的神经元基因表达；携带脑啡肽的AAV载体经心内给药后，可广泛地提高AD实验小鼠脑内脑啡肽含量，降低Aβ寡聚体含量，同时缓解学习记忆功能异常，减轻淀粉样蛋白蓄积所致的大脑负担增高。研究者发现外源性脑啡肽主要存在于核内体，由此认为，AAV载体介导脑啡肽基因有效地清出了脑内的Aβ。

Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice
ABSTRACT
Accumulation of amyloid-β peptide (Aβ) in the brain is closely associated with cognitive decline in Alzheimer's disease (AD). Stereotaxic infusion of neprilysin-encoding viral vectors into the hippocampus has been shown to decrease Aβ in AD-model mice, but more efficient and global delivery is necessary to treat the broadly distributed burden in AD. Here we developed an adeno-associated virus (AAV) vector capable of providing neuronal gene expression throughout the brains after peripheral administration. A single intracardiac administration of the vector carrying neprilysin gene in AD-model mice elevated neprilysin activity broadly in the brain, and reduced Aβ oligomers, with concurrent alleviation of abnormal learning and memory function and improvement of amyloid burden. The exogenous neprilysin was localized mainly in endosomes, thereby effectively excluding Aβ oligomers from the brain. AAV vector-mediated gene transfer may provide a therapeutic strategy for neurodegenerative diseases, where global transduction of a therapeutic gene into the brain is necessary.