长潜伏期是导致临床阿尔兹海默病(AD)治疗错失良机的主要原因，但其详细的分子机制仍然未知。我们前期已证实单核细胞募集可缓解神经炎症，改善中晚期AD认知缺陷。这是否参与延长AD潜伏期？机制是什么？我们近期的预实验发现：AD病理早期，模型小鼠脑内预警素IL-33表达逐渐升高，但随病程进展而下降；伴随IL-33信号减弱，脑内Aβ含量增多，外周单核细胞募集减少。这提示早期IL-33上调可能会延缓AD疾病进展。因此，我们提出科学假设：在AD早期，脑内IL-33信号被激活，并募集、调教单核细胞，甚至T细胞分化，从而延缓疾病进展，延长AD的潜伏期。本项目拟构建IL-33基因敲除的AD模型小鼠，观察早期Aβ病理、神经炎症和认知缺陷的进展，分析IL-33下调对单核细胞和Treg细胞募集和分型的影响，证实IL-33延长AD潜伏期的机制，为全面认识AD的病理生理过程和临床药物开发提供理论依据。

The long latent phase of Alzheimer’s disease (AD) induces the deprivation of a right time for clinical treatment. However, which factors controlling the latent phase in AD are poorly understood. We have demonstrated that recruited monocytes contribute to alleviating neuroinflammation and cognitive deficits in AD. It is still unknown whether they play roles in controlling the latent phase. Here, we found that high levels of IL-33 in the brain of early-stage AD mice, conversely, it decreased in later. With the decrease of IL-33 expression, we found the elevation of Aβaggravation while the inhibition of monocytes recruitment to the diseased brain. IL-33 might delay disease progression during early-stage AD. Therefore, we hypothesized that activated IL-33 signaling during early stage can delay disease progression by recruiting and educating monocytes and T cells to the brain of APP/PS1 mice. In the present study, we will use the IL-33-/-APP/PS1 mice to investigate AD-like pathology and cognitive decline. Furthermore, we will observe the recruitment and polarization of monocytes and Tregs in the brain of early-stage APP/PS1 mice. Collectively, our study will demonstrate the potential underlying mechanisms by which IL-33 delays the progression of AD. It is helpful to understand the pathophysiological process of AD and to direct the clinical anti-AD drug development.