title: TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice.
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.affiliation: 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.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jun-Shan
authors.initials: JS
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Shi
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. jintai.yu@ucsf.edu.
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D053764:Presenilin-1; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse
keywords: Aging; Alzheimer’s disease; Amyloid-β; Cognitive impairment; Microglia; Phagocytosis; TREM2