Cui Feilun, Xu Zhipeng, Lv Yumei, Hu Jianpeng
Department of Urology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
Department of Health Management Section, Zhenjiang College, Zhenjiang, China.
Ann Transl Med. 2021 Sep;9(18):1432. doi: 10.21037/atm-21-4064.
Aberrant growth and polarization of microglia are critical for pathological initiation and progression of neurodegenerative conditions like Alzheimer's disease (AD). However, the molecular signals that govern the outgrowth of microglia have not yet been fully determined. Spindle pole body component 25 (SPC25) is an important part for forming NDC80 complex, which plays a key role in the assembly of the microtubule-binding domain of kinetochores. Nevertheless, the role of SPC25 in microglial growth during neurodegeneration has not been described before, and was thus addressed in the current study.
We generated an adeno-associated virus (AAV) serotype PHP.B carrying short hairpin RNA (shRNA) for SPC25 (shSPC25) under a microglia-specific TMEM119 promoter (AAV-pTMEM-shSPC25). Serotype PHP.B allowed the virus to cross blood-brain barrier, while TMEM119 promoter allowed specific targeting microglia in vitro and in vivo. We intravenously administrated AAV-pTMEM-shSPC25 to AD-prone APP/PS1 male and female mice and determined this effect on microglia proliferation and mouse behavior.
Depletion of SPC25 did not alter polarization of microglia cell polarization in vitro. On the other hand, AD-prone APP/PS1 mice that had received AAV-pTMEM-shSPC25 significantly decreased SPC25 levels in microglia and attenuated microglia proliferation, resulting in significant improvement of the performance of the mice in behavior tests.
Specific depletion of SPC25 in microglia may prevent AD development through suppression of microglia outgrowth. SPC25 may be a promising novel target for preventing AD through microglia.
小胶质细胞的异常生长和极化对于阿尔茨海默病（AD）等神经退行性疾病的病理起始和进展至关重要。然而，调控小胶质细胞生长的分子信号尚未完全明确。纺锤极体组分25（SPC25）是形成NDC80复合体的重要部分，该复合体在动粒微管结合域的组装中起关键作用。然而，SPC25在神经退行性变过程中小胶质细胞生长中的作用此前尚未见报道，因此本研究对其进行了探讨。
我们构建了一种腺相关病毒（AAV）血清型PHP.B，其在小胶质细胞特异性的TMEM119启动子（AAV-pTMEM-shSPC25）控制下携带针对SPC25的短发夹RNA（shRNA）。血清型PHP.B使病毒能够穿越血脑屏障，而TMEM119启动子允许在体外和体内特异性靶向小胶质细胞。我们将AAV-pTMEM-shSPC25静脉注射到易患AD的APP/PS1雄性和雌性小鼠体内，并确定其对小胶质细胞增殖和小鼠行为的影响。
SPC25的缺失在体外并未改变小胶质细胞的极化。另一方面，接受AAV-pTMEM-shSPC25的易患AD的APP/PS1小鼠小胶质细胞中SPC25水平显著降低，小胶质细胞增殖减弱，导致小鼠在行为测试中的表现显著改善。
小胶质细胞中SPC25的特异性缺失可能通过抑制小胶质细胞生长来预防AD的发展。SPC25可能是通过小胶质细胞预防AD的一个有前景的新靶点。
