Regen Francesca, Hellmann-Regen Julian, Costantini Erica, Reale Marcella
Department of Psychiatry, Section Clinical Neurobiology, Campus Benjamin Franklin, Charite, University Medicine, Berlin. Germany.
Department of Medical, Oral and Biotechnological Science, University "G. d'Annunzio" Chieti- Pescara, Chieti. Italy.
Curr Alzheimer Res. 2017;14(11):1140-1148. doi: 10.2174/1567205014666170203141717.
Microglial activation is a hallmark of neuroinflammation, seen in most acute and chronic neuropsychiatric conditions. With growing knowledge about microglia functions in surveying the brain for alterations, microglial activation is increasingly discussed in the context of disease progression and pathogenesis of Alzheimer's disease (AD). Underlying molecular mechanisms, however, remain largely unclear. While proper microglial function is essentially required for its scavenging duties, local activation of the brain's innate immune cells also brings about many less advantageous changes, such as reactive oxygen species (ROS) production, secretion of proinflammatory cytokines or degradation of neuroprotective retinoids, and may thus unnecessarily put surrounding healthy neurons in danger. In view of this dilemma, it is little surprising that both, AD vaccination trials, and also immunosuppressive strategies have consistently failed in AD patients. Nevertheless, epidemiological evidence has suggested a protective effect for anti-inflammatory agents, supporting the hypothesis that key processes involved in the pathogenesis of AD may take place rather early in the time course of the disorder, likely long before memory impairment becomes clinically evident. Activation of microglia results in a severely altered microenvironment. This is not only caused by the plethora of secreted cytokines, chemokines or ROS, but may also involve increased turnover of neuroprotective endogenous substances such as retinoic acid (RA), as recently shown in vitro.
We discuss findings linking microglial activation and AD and speculate that microglial malfunction, which brings about changes in local RA concentrations in vitro, may underlie AD pathogenesis and precede or facilitate the onset of AD. Thus, chronic, "innate neuroinflammation" may provide a valuable target for preventive and therapeutic strategies.
小胶质细胞激活是神经炎症的一个标志，在大多数急性和慢性神经精神疾病中都可见到。随着对小胶质细胞在监测大脑变化方面功能的了解不断增加，小胶质细胞激活在阿尔茨海默病（AD）的疾病进展和发病机制背景下的讨论越来越多。然而，潜在的分子机制在很大程度上仍不清楚。虽然小胶质细胞的正常功能对于其清除职责至关重要，但大脑固有免疫细胞的局部激活也会带来许多不利变化，如活性氧（ROS）产生、促炎细胞因子分泌或神经保护性视黄醇的降解，从而可能不必要地使周围健康神经元处于危险之中。鉴于这种困境，AD疫苗试验和免疫抑制策略在AD患者中一直失败也就不足为奇了。尽管如此，流行病学证据表明抗炎药物具有保护作用，支持了AD发病机制中关键过程可能在疾病进程的早期发生，可能早在记忆障碍在临床上变得明显之前就已发生的假说。小胶质细胞的激活导致微环境严重改变。这不仅是由大量分泌的细胞因子、趋化因子或ROS引起的，还可能涉及神经保护性内源性物质如视黄酸（RA）的周转增加，正如最近在体外研究中所示。
我们讨论了将小胶质细胞激活与AD联系起来的研究结果，并推测小胶质细胞功能障碍在体外会导致局部RA浓度变化，这可能是AD发病机制的基础，并先于或促进AD的发病。因此，慢性“固有神经炎症”可能为预防和治疗策略提供有价值的靶点。
