| Summary: | 碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 101 === Alzheimer's disease (AD) is the most common neurodegenerative disease. The major pathological hallmark is the accumulation of amyloid plaques, consisting of aggregated amyloid-β (Aβ). Aβ overexpression not only results in synapses degeneration and neurons damage, but also recruits and stimulates microglia. Activated microglia secrets proinflammatory cytokines and ROS to induce inflammation and further neuron injury. Triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia has been reported to be associated with AD. TREM2 is upregulated in amyloid plaque-associated microglia in aged AD mouse models. Besides, AD-patient genome sequence analysis indicated that rare variants in TREM2 are associated with a significant increase in the risk of AD. Therefore, we assumed that TREM2 plays a role in modulating the neuroinflammation of AD. By adapting the J20 APP-transgenic model in Trem2-deficient mice, we demonstrated that depletion of TREM2 rescued the behavioral impairments of J20 mice. Microglia IBA-I and iNOS expression, as well as the local Aβ deposition were decreased in the brain tissues of J20 mice with TREM2 deficiency. Furthermore, TREM2 could interact with fibrillar Aβ and oligomer Αβ in vitro. Finally we found that TREM2 deficiency had no effect on Aβ binding and internalization, but moderately suppressed the degradation of Aβ in bone marrow-derived macrophages (BMDMs). By contrast, the iNOS mRNA and protein expression, as well as the IL-6 and TNF-α mRNA inductions were suppressed in Aβ-stimulated Trem2-deficient BMDMs. These results suggested that TREM2 mediates Aβ-triggered proinflammatory activation and also involves in regulating Aβ clearance in microglia. Therefore, TREM2 could be a potential target for developing novel therapeutics for AD.
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