Faculty of Medicine, School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong.
Brain Research Centre, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
Molecules. 2021 May 4;26(9):2685. doi: 10.3390/molecules26092685.
Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for Alzheimer's disease (AD). However, findings on the effects of TREM2 on Aβ deposition are quite inconsistent in animal studies, requiring further investigation. In this study, we investigated whether elevation of TREM2 mitigates Aβ pathology in TgCRND8 mice. We found that peripheral nerve injury resulted in a robust elevation of TREM2 exclusively in reactive microglia in the ipsilateral spinal cord of aged TgCRND8 mice at the age of 20 months. TREM2 expression appeared on day 1 post-injury and the upregulation was maintained for at least 28 days. Compared to the contralateral side, neither amyloid beta plaque load nor soluble Aβ40 and Aβ42 levels were attenuated upon TREM2 induction. We further showed direct evidence that TREM2 elevation in reactive microglia did not affect amyloid-β pathology in plaque-bearing TgCRND8 mice by applying anti-TREM2 neutralizing antibody to selectively block TREM2. Our results question the ability of TREM2 to ameliorate established Aβ pathology, discouraging future development of disease-modifying pharmacological treatments targeting TREM2 in the late stage of AD.
几项遗传研究已经确定触发受体表达在髓样细胞 2（TREM2）的罕见变体是阿尔茨海默病（AD）的风险因素。然而，在动物研究中，关于 TREM2 对 Aβ沉积的影响的发现相当不一致，需要进一步研究。在这项研究中，我们研究了 TREM2 的升高是否减轻了 TgCRND8 小鼠的 Aβ病理。我们发现，周围神经损伤导致 20 个月大的老年 TgCRND8 小鼠对侧脊髓中的反应性小胶质细胞中 TREM2 的强烈升高。TREM2 的表达在损伤后第 1 天出现，上调至少维持 28 天。与对侧相比，TREM2 诱导后，淀粉样β斑块负荷或可溶性 Aβ40 和 Aβ42 水平均未降低。我们进一步通过应用抗 TREM2 中和抗体选择性阻断 TREM2，直接证明了反应性小胶质细胞中 TREM2 的升高并未影响斑块携带的 TgCRND8 小鼠中的淀粉样-β病理。我们的结果质疑了 TREM2 改善已建立的 Aβ病理的能力，这阻碍了针对 AD 晚期的 TREM2 的疾病修饰药物治疗的未来发展。
