Microglial Priming and Alzheimer's Disease: A Possible Role for (Early) Immune Challenges and Epigenetics?
Microglial Priming and Alzheimer's Disease: A Possible Role for (Early) Immune Challenges and Epigenetics?
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DOI：
10.3389/fnhum.2016.00398
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发表时间：
2016
影响因子：
2.9
通讯作者：
Korosi A
中科院分区：
文献类型：
--
作者：
Hoeijmakers L;Heinen Y;van Dam AM;Lucassen PJ;Korosi A
神经炎症被认为有助于阿尔茨海默病（AD）的发病机制，这在很大程度上是由小胶质细胞介导的。鉴于免疫系统和大脑之间的紧密相互作用，外周免疫挑战可以深刻地影响大脑功能。事实上，临床前和临床研究都表明，异常的炎症反应会导致行为障碍和认知缺陷，特别是当大脑处于脆弱状态时，例如，在早期发育期间，由于衰老，或在AD等疾病条件下。然而，外周免疫挑战究竟如何影响大脑功能，以及这是否由异常的小胶质细胞功能介导，在很大程度上仍然是难以捉摸的。在这篇综述中，我们假设：(1)在生命脆弱时期发生的系统性免疫挑战可能增加诱导后期认知功能障碍的倾向，并加速AD病理；(2)小胶质细胞的“启动”在介导这种脆弱性方面起着重要作用。我们强调了小胶质细胞是如何被新生儿感染和衰老所激活的，在这两个生命阶段，小胶质细胞的活性被特异性上调。特定小胶质细胞表型（比例）的持续变化可导致对随后的炎症挑战的夸大的促炎细胞因子反应。虽然脑功能的变化最初是短暂的，但这种促炎细胞因子的持续和/或过量释放可以激活已知与AD相关的各种下游细胞级联反应。最后，我们讨论了小胶质细胞启动和异常小胶质细胞反应作为阿尔茨海默病治疗策略的潜在靶点。
Neuroinflammation is thought to contribute to Alzheimer’s disease (AD) pathogenesis that is, to a large extent, mediated by microglia. Given the tight interaction between the immune system and the brain, peripheral immune challenges can profoundly affect brain function. Indeed, both preclinical and clinical studies have indicated that an aberrant inflammatory response can elicit behavioral impairments and cognitive deficits, especially when the brain is in a vulnerable state, e.g., during early development, as a result of aging, or under disease conditions like AD. However, how exactly peripheral immune challenges affect brain function and whether this is mediated by aberrant microglial functioning remains largely elusive. In this review, we hypothesize that: (1) systemic immune challenges occurring during vulnerable periods of life can increase the propensity to induce later cognitive dysfunction and accelerate AD pathology; and (2) that “priming” of microglial cells is instrumental in mediating this vulnerability. We highlight how microglia can be primed by both neonatal infections as well as by aging, two periods of life during which microglial activity is known to be specifically upregulated. Lasting changes in (the ratios of) specific microglial phenotypes can result in an exaggerated pro-inflammatory cytokine response to subsequent inflammatory challenges. While the resulting changes in brain function are initially transient, a continued and/or excess release of such pro-inflammatory cytokines can activate various downstream cellular cascades known to be relevant for AD. Finally, we discuss microglial priming and the aberrant microglial response as potential target for treatment strategies for AD.