Jiang Teng, Wan Yu, Zhang Ying-Dong, Zhou Jun-Shan, Gao Qing, Zhu Xi-Chen, Shi Jian-Quan, Lu Huan, Tan Lan, Yu Jin-Tai
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
Mol Neurobiol. 2017 Mar;54(2):855-865. doi: 10.1007/s12035-016-9704-x. Epub 2016 Jan 16.
Previously, we showed that overexpression of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific immune receptor, in the brain of a middle-aged (7 months old) APPswe/PS1dE9 mice could ameliorate Alzheimer's disease (AD)-related neuropathology by enhancement of microglial amyloid-β (Aβ) phagocytosis. Since AD is an age-related neurodegenerative disorder, it is critical to assess the efficacy of TREM2 overexpression in aging animals with an advanced disease stage. In vivo, we employed a lentiviral strategy to overexpress TREM2 in the brain of aging (18 months old) APPswe/PS1dE9 mice, and observed its efficacy on AD-related neuropathology and cognitive functions. Afterwards, we directly isolated microglia from middle-aged and aging APPswe/PS1dE9 mice and determined effects of TREM2 overexpression on microglial Aβ phagocytosis and Aβ-binding receptors expression in vitro. In aging APPswe/PS1dE9 mice, TREM2 overexpression has no beneficial effect on AD-related neuropathology and spatial cognitive functions. Of note, in vitro experiments showed a significant reduction of Aβ phagocytosis in microglia from aging APPswe/PS1dE9 mice, possibly attributing to the declined expression of Aβ-binding receptors. Meanwhile, this phagocytic deficit in microglia from aging APPswe/PS1dE9 mice cannot be rescued by TREM2 overexpression. Taken together, our study shows that TREM2 overexpression fails to provide neuroprotection in aging APPswe/PS1dE9 mice, possibly attributing to deficits in microglial Aβ phagocytosis at the late-stage of disease progression. These findings indicate that TREM2-mediated protection in AD is at least partially dependent on the reservation of microglial phagocytic functions, emphasizing the importance of early therapeutic interventions for this devastating disease.
此前，我们发现，在中年（7月龄）APPswe/PS1dE9小鼠脑内过表达髓样细胞触发受体2（TREM2，一种小胶质细胞特异性免疫受体），可通过增强小胶质细胞对淀粉样β（Aβ）的吞噬作用来改善阿尔茨海默病（AD）相关神经病理学变化。由于AD是一种与年龄相关的神经退行性疾病，因此评估TREM2过表达在疾病晚期的老龄动物中的疗效至关重要。在体内实验中，我们采用慢病毒策略在老龄（18月龄）APPswe/PS1dE9小鼠脑内过表达TREM2，并观察其对AD相关神经病理学变化和认知功能的影响。之后，我们直接从中年和老龄APPswe/PS1dE9小鼠中分离出小胶质细胞，并在体外确定TREM2过表达对小胶质细胞Aβ吞噬作用和Aβ结合受体表达的影响。在老龄APPswe/PS1dE9小鼠中，TREM2过表达对AD相关神经病理学变化和空间认知功能没有有益影响。值得注意的是，体外实验显示，老龄APPswe/PS1dE9小鼠小胶质细胞对Aβ的吞噬作用显著降低，这可能归因于Aβ结合受体表达的下降。同时，老龄APPswe/PS1dE9小鼠小胶质细胞的这种吞噬缺陷不能通过TREM2过表达来挽救。综上所述，我们的研究表明，TREM2过表达未能在老龄APPswe/PS1dE9小鼠中提供神经保护作用，这可能归因于疾病进展后期小胶质细胞Aβ吞噬功能的缺陷。这些发现表明，TREM2在AD中的保护作用至少部分依赖于小胶质细胞吞噬功能的保留，强调了对这种毁灭性疾病进行早期治疗干预的重要性。
