Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
Pahnke Laboratory (Drug Development and Chemical Biology), Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck and University Medical Center Schleswig-Holstein, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Biomolecules. 2023 Feb 9;13(2):331. doi: 10.3390/biom13020331.
Alzheimer's disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition.
阿尔茨海默病（AD）是痴呆症最常见的病因。芬戈莫德先前在不同的 AD 动物模型中显示出有益的效果。然而，当它在疾病早期阶段应用时，却显示出矛盾的效果。我们的目的是评估芬戈莫德在两种不同的治疗模式中的作用。为了实现这一目标，我们用 APP 转基因小鼠进行了为期 50 天的治疗，起始时间分别为 50 天龄（早期）或 125 天龄（晚期）时开始。为了评估效果，我们研究了神经炎症和神经胶质标志物、Aβ 负荷以及脑源性神经营养因子（BDNF）的浓度。我们发现，只有在晚期治疗模式的雄性动物中，Aβ 负荷降低。这些动物的小胶质细胞激活和 IL-1β 也减少。与对照组相比，其他治疗组没有任何差异。另一方面，我们检测到 BDNF 与大脑 Aβ 浓度之间存在线性相关性。芬戈莫德治疗在 AD 模型中显示出有益的效果，但结果取决于治疗开始时的神经炎症状态。因此，根据我们的数据，在出现第一个 AD 症状后，芬戈莫德治疗可能会有效，主要影响对持续 Aβ 沉积的神经炎症反应。
