Department of Comparative Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA.
Department of Pharmacology, School of Medicine, University of Nis, Nis, Serbia.
J Alzheimers Dis. 2022;88(3):837-847. doi: 10.3233/JAD-210041.
Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown.
Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology.
Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia.
Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function.
Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations.
触发髓系细胞表达的受体-2（TREM2）的基因突变与阿尔茨海默病（AD）和其他进行性痴呆的风险增加密切相关。在大脑中，TREM2 蛋白特异性表达于小胶质细胞，提示其在驱动疾病病理学方面的积极参与。使用各种转基因 AD 模型通过 TREM2 干扰小胶质细胞功能，最近的几项研究提供了重要数据，表明 TREM2 与潜在的淀粉样蛋白-β（Aβ）和 tau 病理学之间存在因果关系。然而，TREM2 增加 AD 临床易感性并影响其进展的机制仍在很大程度上未知。
我们的目的是阐明 TREM2 对与 AD 病理生理学相关的特定振荡动态变化的潜在贡献。
使用自发和桥脑核桥脑嘴刺激诱导的海马振荡范式，在乌拉坦麻醉下研究 TREM2 单倍不足 TREM2（Het）或完全缺失 TREM2（Hom）对野生型和 Aβ过表达 Tg2576 小鼠海马网络功能的影响。
TREM2 的部分（TREM2（Het））或完全（TREM2（Hom））缺失导致野生型和 Tg2576 小鼠自发癫痫样发作的发生率增加。重要的是，与野生型小鼠相比，Tg2576 小鼠中 TREM2 的缺失显著降低了由脑干刺激引起的海马中θ振荡的功率。然而，它对海马θ相γ幅度耦合没有显著影响，因为无论 TREM2 功能如何，在 Tg2576 小鼠中发现耦合减少了 60%以上。
我们的研究结果表明，TREM2 依赖的小胶质细胞功能在野生型和 Aβ过表达小鼠的海马神经元兴奋性中起作用，而 TREM2 功能的缺失加剧了 Aβ对海马网络振荡的破坏作用。
