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TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice

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Abstract

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.

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    Authors and Affiliations

    1. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

      Teng Jiang, Ying-Dong Zhang, Jun-Shan Zhou, Qing Gao & Jian-Quan Shi

    2. Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA

      Teng Jiang & Jin-Tai Yu

    3. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China

      Yu Wan & Lan Tan

    4. Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China

      Xi-Chen Zhu, Huan Lu & Lan Tan

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    1. Teng Jiang
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    Correspondence to Teng Jiang, Lan Tan or Jin-Tai Yu.

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    Conflict of Interest

    The authors declare no conflict of interest. This work was supported by National Natural Science Foundation of China to T.J. (81501092), J.T.Y. (81471309), L.T. (81571245), and J.Q.S. (81500916); Natural Science Foundation of Jiangsu Province to T.J. (BK20150091) and Y.D.Z. (BK20151084); China Postdoctoral Science Foundation to T.J. (2015M580448); Qingdao Key Health Discipline Development Fund; Qingdao Outstanding Health Professional Development Fund; and Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders.

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    Teng Jiang and Yu Wan contributed equally to this work.

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    Fig. S1

    Overexpression of TREM2 in brain of aging APPswe/PS1dE9 mice using a lentiviral strategy. a, b The mRNA levels of Trem2 and Tyrobp in cerebral cortex were detected by qRT-PCR at 2 months after lentiviral particle injection. It should be noted that the mRNA level of Tyrobp in cerebral cortex was not affected by TREM2 overexpression. Data were normalized to the levels of Gapdh mRNA. c, d The mRNA levels of Trem2 and Tyrobp in hippocampus were detected by qRT-PCR at 2 months after lentiviral particle injection. It should be noted that the mRNA level of Tyrobp in hippocampus was not affected by TREM2 overexpression. Data were normalized to the levels of Gapdh mRNA. All data were analyzed by one-way ANOVA followed by Tukey’s post hoc test. Columns represent mean ± s.d. (n = 6 per group). *P < 0.05 (GIF 466 kb)

    High resolution image (TIF 463 kb)

    Fig. S2

    Overexpression of TREM2 expression in primary microglia isolated from middle-aged and aging APPswe/PS1dE9 mice using a lentiviral strategy. The mRNA levels of Trem2 and Tyrobp in adult microglia were detected by qRT-PCR at 72 h after transfection. It should be noted that the mRNA level of Tyrobp was not affected by TREM2 overexpression. Data were normalized to the levels of Gapdh mRNA. All data were analyzed by one-way ANOVA followed by Tukey’s post hoc test. Columns represent mean ± s.d. *P < 0.05 (GIF 293 kb)

    High resolution image (TIF 422 kb)

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    Jiang, T., Wan, Y., Zhang, YD. et al. TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice. Mol Neurobiol 54, 855–865 (2017). https://doi.org/10.1007/s12035-016-9704-x

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