Department of Cellular and Network Neurobiology, Institute of Experimental Medicine, HAS, Budapest, Hungary.
János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary.
PLoS One. 2020 May 29;15(5):e0233700. doi: 10.1371/journal.pone.0233700. eCollection 2020.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (Aβ) depositions generated by the proteolysis of amyloid precursor protein (APP) in the brain. In APPNL-F mice, APP gene was humanized and contains two familial AD mutations, and APP-unlike other mouse models of AD-is driven by the endogenous mouse APP promoter. Similar to people without apparent cognitive dysfunction but with heavy Aβ plaque load, we found no significant decline in the working memory of adult APPNL-F mice, but these mice showed decline in the expression of normal anxiety. Using immunohistochemistry and 3D block-face scanning electron microscopy, we found no changes in GABAA receptor positivity and size of somatic and dendritic synapses of hippocampal interneurons. We did not find alterations in the level of expression of perineuronal nets around parvalbumin (PV) interneurons or in the density of PV- or somatostatin-positive hippocampal interneurons. However, in contrast to other investigated cell types, PV interneuron axons were occasionally mildly dystrophic around Aβ plaques, and the synapses of PV-positive axon initial segment (AIS)-targeting interneurons were significantly enlarged. Our results suggest that PV interneurons are highly resistant to amyloidosis in APPNL-F mice and amyloid-induced increase in hippocampal pyramidal cell excitability may be compensated by PV-positive AIS-targeting cells. Mechanisms that make PV neurons more resilient could therefore be exploited in the treatment of AD for mitigating Aβ-related inflammatory effects on neurons.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是认知能力下降和大脑中淀粉样前体蛋白（APP）的蛋白水解产生的淀粉样β（Aβ）沉积。在 APPNL-F 小鼠中，APP 基因被人源化并包含两种家族性 AD 突变，并且 APP 与 AD 的其他小鼠模型不同，它由内源性小鼠 APP 启动子驱动。与没有明显认知功能障碍但有大量 Aβ斑块负荷的人相似，我们没有发现成年 APPNL-F 小鼠的工作记忆有明显下降，但这些小鼠表现出正常焦虑表达的下降。通过免疫组织化学和 3D 块面扫描电子显微镜，我们没有发现海马中间神经元的 GABAA 受体阳性和体树突突触的大小发生变化。我们没有发现围绕钙结合蛋白（PV）中间神经元的周围神经网或 PV 或生长抑素阳性海马中间神经元密度的表达水平发生改变。然而，与其他研究的细胞类型不同，PV 中间神经元轴突偶尔在 Aβ斑块周围轻度营养不良，并且靶向 PV 阳性轴突起始段（AIS）的中间神经元的突触明显增大。我们的结果表明，PV 中间神经元在 APPNL-F 小鼠中对淀粉样变性具有高度抗性，并且淀粉样蛋白诱导的海马锥体神经元兴奋性增加可能被靶向 PV 阳性 AIS 的细胞所代偿。因此，使 PV 神经元更具弹性的机制可用于 AD 的治疗，以减轻 Aβ 对神经元的炎症相关影响。
