唐氏综合征（Down syndrome，DS）患儿不仅有精神发育迟滞，而且呈现与年龄相关的神经退行性病变。目前对其机制缺乏认识。本课题组前期研究发现DS患儿血浆维生素A（Vitamin A, VA）水平明显降低，RARα表达水平明显降低，且VA可通过RARα调控PI3K/AKT信号通路。而PI3K/AKT信号通路参与Aβ的产生和血脑屏障完整性的维持。因此，我们在前期工作基础上，拟利用VA缺乏和VA补充的DS模型鼠并通过体外培养其海马神经元，利用过表达和沉默RARɑ，阻断和激动PI3K的手段，从体内体外两方面论证RA通过PI3K/Akt一方面调节ADAM10表达，进而影响Aβ生成；另一方面活化GSK-3β、BAD,参与维持血脑屏障紧密连接的完整性，进而减少Aβ入脑沉积。为DS神经退行性病变的认识提供新的视角，并为后续的干预实验打下基础。

Down syndrome (DS) patients not only show mental retardation, but also reveal age-related neurodegeneration. However, the mechanism has not been elucidated. Previous work from out group have demonstrated a significant decrease of serum Vitamin A (VA) in DS patients, accompanied by decreased RARα expression. Moreover, VA regulation of PI3K/Akt signaling pathway is mediated by RARα, which is involved in Amyloid β peptide (Aβ) generation and blood brain barrier (BBB) integrity maintenance. Therefore, based on the preliminary data, we plan to overexpress and knockdown RARα, or antagonize and stimulate PI3K in either DS mouse or cultured hippocampal neurons from VA-deficient and VA-supplemented DS mouse. We hypothesize that RA regulates ADAM10 expression through PI3K/Akt pathway to affect Aβ generation. In addition, RA could activate GSK-3β and BAD to maintain BBB integrity, and further alleviate Aβ precipitation in the brain. This work could provide a new perspective for neurodegeneration disease study, and theoretical basis for later intervention study.