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TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice.
Mol Neurobiol. 2017 03; 54(2):855-865.MN

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.

Authors+Show Affiliations

Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. jt870918@163.com. Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. jt870918@163.com.Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China. dr.tanlan@163.com. Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China. dr.tanlan@163.com.Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. jintai.yu@ucsf.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26780455

Citation

Jiang, Teng, et al. "TREM2 Overexpression Has No Improvement On Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice." Molecular Neurobiology, vol. 54, no. 2, 2017, pp. 855-865.
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. 2017;54(2):855-865.
Jiang, T., Wan, Y., Zhang, Y. D., Zhou, J. S., Gao, Q., Zhu, X. C., Shi, J. Q., Lu, H., Tan, L., & Yu, J. T. (2017). TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice. Molecular Neurobiology, 54(2), 855-865. https://doi.org/10.1007/s12035-016-9704-x
Jiang T, et al. TREM2 Overexpression Has No Improvement On Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice. Mol Neurobiol. 2017;54(2):855-865. PubMed PMID: 26780455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice. AU - Jiang,Teng, AU - Wan,Yu, AU - Zhang,Ying-Dong, AU - Zhou,Jun-Shan, AU - Gao,Qing, AU - Zhu,Xi-Chen, AU - Shi,Jian-Quan, AU - Lu,Huan, AU - Tan,Lan, AU - Yu,Jin-Tai, Y1 - 2016/01/16/ PY - 2015/09/14/received PY - 2016/01/05/accepted PY - 2016/1/19/pubmed PY - 2018/2/14/medline PY - 2016/1/19/entrez KW - Aging KW - Alzheimer’s disease KW - Amyloid-β KW - Cognitive impairment KW - Microglia KW - Phagocytosis KW - TREM2 SP - 855 EP - 865 JF - Molecular neurobiology JO - Mol. Neurobiol. VL - 54 IS - 2 N2 - 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. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/26780455/TREM2_Overexpression_has_No_Improvement_on_Neuropathology_and_Cognitive_Impairment_in_Aging_APPswe/PS1dE9_Mice_ L2 - https://dx.doi.org/10.1007/s12035-016-9704-x DB - PRIME DP - Unbound Medicine ER -