Yu Linjie, Liu Yi, Yang Hui, Zhu Xiaolei, Cao Xiang, Gao Jun, Zhao Hui, Xu Yun
Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P. R. China.
The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, P. R. China.
J Alzheimers Dis. 2017;59(3):913-927. doi: 10.3233/JAD-170320.
Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated. The open field test, Morris water maze test, and fear condition test revealed that PSD-93 overexpression ameliorated spatial memory deficits in APP/PS1 mice. The facilitation of long-term potentiation induction was observed in APP/PS1 mice after PSD-93 overexpression. The expression of somatostatin receptor 4 (SSTR4) and neprilysin was increased, while the amyloid plaque load and Aβ levels were decreased in the brains of APP/PS1 mice. Moreover, PSD-93 interacted with SSTR4 and affected the level of SSTR4 on cell membrane, which was associated with the ubiquitination. Together, these findings suggest that PSD-93 attenuates spatial memory deficits and decreases amyloid levels in APP/PS1 mice, which might be associated with Aβ catabolism, and overexpression of PSD-93 might be a potential therapy for AD.
淀粉样蛋白β（Aβ）是阿尔茨海默病（AD）的关键神经病理学标志。突触后致密蛋白93（PSD-93）是一种富集于突触后位点的关键支架蛋白。本研究的目的是通过降低大脑中的Aβ水平，研究PSD-93过表达是否能减轻Aβ诱导的APPswe/PS1dE9（APP/PS1）小鼠的认知功能障碍。与野生型小鼠相比，6月龄APP/PS1小鼠海马中PSD-93水平显著降低。在慢病毒介导的PSD-93过表达后，对认知功能、突触功能和淀粉样蛋白负荷进行了研究。旷场试验、莫里斯水迷宫试验和恐惧条件试验表明，PSD-93过表达改善了APP/PS1小鼠的空间记忆缺陷。PSD-93过表达后，在APP/PS1小鼠中观察到长时程增强诱导的促进作用。APP/PS1小鼠大脑中生长抑素受体4（SSTR4）和中性内肽酶的表达增加，而淀粉样斑块负荷和Aβ水平降低。此外，PSD-93与SSTR4相互作用并影响细胞膜上SSTR4的水平，这与泛素化有关。总之，这些发现表明，PSD-93减轻了APP/PS1小鼠的空间记忆缺陷并降低了淀粉样蛋白水平，这可能与Aβ分解代谢有关，PSD-93过表达可能是AD的一种潜在治疗方法。
