School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China.
Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.
J Alzheimers Dis. 2019;67(1):169-179. doi: 10.3233/JAD-180823.
Alzheimer's disease (AD) is characterized by progressive loss of memory and other cognitive functions. Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau are two major neuropathological features of AD. Formyl peptide receptor 2 (FPR2), contributing to innate immunity and inflammation, has been implicated in the uptake and clearance of Aβ. It remains unclear whether FPR2 affects cognition and tau phosphorylation. The effects of FPR2 in cognition and tau phosphorylation were examined using FPR2 knock-out (Fpr2-/-) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The general behaviors and cognitive functions were evaluated using rotarod, open field test, and Morris water maze test. The alteration in tau hyperphosphorylation and activation of astrocytes were determined by using western blotting and/or immunofluorescence staining. ICV injection of STZ impaired spatial learning and memory of mice in Morris water maze. FPR2 deficiency improved spatial learning and memory of ICV-STZ mice. In the hippocampus and cortex of ICV-STZ mice, a marked increase was observed in tau phosphorylation at Ser199, Thr205, and Ser396 compared with ICV-saline control mice. However, FPR2 deficiency attenuated the hyperphosphorylation of tau at Ser199 and Ser396. In addition, the expression of GFAP was significantly increased in hippocampus and cortex of ICV-STZ mice. FPR2 deletion reduced the increase of GFAP expression induced by ICV injection of STZ. These results indicate that FPR2 deficiency is associate with improved cognition, reduced tau hyperphosphorylation, and activation of astrocytes in the mouse AD model tested. FPR2 may be a potential target in AD prevention and therapy.
阿尔茨海默病（AD）的特征是记忆和其他认知功能的进行性丧失。淀粉样蛋白-β（Aβ）和过度磷酸化的 tau 是 AD 的两个主要神经病理学特征。参与先天免疫和炎症的甲酰肽受体 2（FPR2）已被牵连到 Aβ的摄取和清除中。目前尚不清楚 FPR2 是否会影响认知和 tau 磷酸化。使用 FPR2 敲除（Fpr2-/-）小鼠通过脑室内（ICV）注射链脲佐菌素（STZ）来检查 FPR2 对认知和 tau 磷酸化的影响。使用转棒、旷场试验和 Morris 水迷宫试验评估一般行为和认知功能。通过 Western blot 和/或免疫荧光染色确定 tau 过度磷酸化和星形胶质细胞激活的变化。ICV 注射 STZ 损害了 Morris 水迷宫中小鼠的空间学习和记忆。FPR2 缺乏改善了 ICV-STZ 小鼠的空间学习和记忆。与 ICV-盐水对照小鼠相比，在 ICV-STZ 小鼠的海马和皮质中观察到 tau 在 Ser199、Thr205 和 Ser396 处的磷酸化明显增加。然而，FPR2 缺乏减轻了 tau 在 Ser199 和 Ser396 处的过度磷酸化。此外，在 ICV-STZ 小鼠的海马和皮质中 GFAP 的表达显著增加。FPR2 缺失减少了 ICV 注射 STZ 诱导的 GFAP 表达增加。这些结果表明，FPR2 缺乏与在测试的 AD 模型中改善认知、减少 tau 过度磷酸化和星形胶质细胞激活有关。FPR2 可能是 AD 预防和治疗的潜在靶点。
