TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice |
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Authors: | Teng Jiang Yu Wan Ying-Dong Zhang Jun-Shan Zhou Qing Gao Xi-Chen Zhu Jian-Quan Shi Huan Lu Lan Tan Jin-Tai Yu |
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Affiliation: | 1.Department of Neurology, Nanjing First Hospital,Nanjing Medical University,Nanjing,China;2.Memory and Aging Center, Department of Neurology,University of California,San Francisco,USA;3.Department of Neurology, Qingdao Municipal Hospital, School of Medicine,Qingdao University,Qingdao,China;4.Department of Neurology, Qingdao Municipal Hospital,Nanjing Medical University,Nanjing,China |
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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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