Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229.
Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229
J Neurosci. 2022 Jul 6;42(27):5294-5313. doi: 10.1523/JNEUROSCI.2427-21.2022. Epub 2022 Jun 7.
The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer's disease (AD) have remained largely uncharacterized. We report that selective loss of , a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, and improved cognitive function in the AD mouse model. Combined loss of and in microglia led to reduced Aβ clearance and increased Aβ plaque burden revealing that Trem2 functions downstream of mTOR. mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. studies using -deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of -deficient microglia with fluorescent-labeled Aβ revealed enhanced Aβ uptake and clearance, which was blunted by rapamycin, an mTOR inhibitor. treatment of mice of relevant genotypes in the background with rapamycin, affected microglial activity, decreased Trem2 expression and reduced Aβ clearance causing an increase in Aβ plaque burden. Prolonged treatment with rapamycin caused even further reduction of mTOR activity, reduction in Trem2 expression, and increase in Aβ levels. Together, our findings reveal that mTOR signaling in microglia is critically linked to Trem2 regulation and lysosomal biogenesis, and that the upregulation of Trem2 in microglia through mTOR activation could be exploited toward better therapeutic avenues to Aβ-related AD pathologies. Mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator for major cellular metabolic processes. However, the link between mTOR signaling and Alzheimer's disease (AD) is not well understood. In this study, we provide compelling evidence that mTOR activation in microglia would benefit β-Amyloid (Aβ)-related AD pathologies, as it upregulates Trem2, a key receptor for Aβ plaque uptake. Inhibition of mTOR pathway with rapamycin, a well-established immunosuppressant, downregulated Trem2 in microglia and reduced Aβ plaque clearance indicating that mTOR inactivation may be detrimental in Aβ-associated AD patients. This finding will have a significant public health impact and benefit, regarding the usage of rapamycin in AD patients, which we believe will aggravate the Aβ-related AD pathologies.
雷帕霉素（mTOR）信号通路的机械靶点在包括代谢和分化在内的关键细胞过程中发挥着重要作用；然而，mTOR 在小胶质细胞中的作用及其在阿尔茨海默病（AD）中的重要性在很大程度上仍未得到充分描述。我们报告说，在雄性和雌性小鼠的小胶质细胞中选择性敲除 mTOR 的负调节剂 ，会导致 mTOR 激活和 Trem2 的上调，从而增强β-淀粉样蛋白（Aβ）清除，减少棘突丢失，并改善 AD 小鼠模型的认知功能。小胶质细胞中 和 的联合缺失导致 Aβ 清除减少和 Aβ 斑块负担增加，表明 Trem2 功能位于 mTOR 下游。 突变的小胶质细胞表现出吞噬作用增强，CD68 和 Lamp1 溶酶体蛋白上调。使用 -缺陷型小胶质细胞进行的研究表明，溶酶体示踪剂指示剂 Green DND-26 的内吞作用增强，表明溶酶体活性增强。用荧光标记的 Aβ 孵育 -缺陷型小胶质细胞可增强 Aβ 的摄取和清除，这一过程被 mTOR 抑制剂雷帕霉素阻断。在 背景下用雷帕霉素处理相关基因型的小鼠会影响小胶质细胞的活性，降低 Trem2 的表达并减少 Aβ 的清除，从而导致 Aβ 斑块负担增加。雷帕霉素的长期治疗甚至会进一步降低 mTOR 的活性，降低 Trem2 的表达，并增加 Aβ 的水平。总的来说，我们的研究结果表明，mTOR 信号通路在小胶质细胞中与 Trem2 调节和溶酶体生物发生密切相关，通过 mTOR 激活上调小胶质细胞中的 Trem2 可能是一种针对与 Aβ 相关的 AD 病理的更好的治疗途径。雷帕霉素（mTOR）信号通路是细胞代谢等主要过程的关键调节剂。然而，mTOR 信号通路与阿尔茨海默病（AD）之间的联系尚不清楚。在这项研究中，我们提供了令人信服的证据，证明 mTOR 在小胶质细胞中的激活有利于β-淀粉样蛋白（Aβ）相关的 AD 病理，因为它上调了 Trem2，Aβ 斑块摄取的关键受体。用雷帕霉素抑制 mTOR 通路，一种已被广泛应用的免疫抑制剂，会下调小胶质细胞中的 Trem2 并减少 Aβ 斑块清除，表明 mTOR 失活在 Aβ 相关 AD 患者中可能是有害的。这一发现将具有重大的公共卫生影响和益处，关于雷帕霉素在 AD 患者中的使用，我们认为这将加重与 Aβ 相关的 AD 病理。
