Group of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), 28041, Madrid, Spain.
Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, Spain.
Acta Neuropathol Commun. 2023 Mar 31;11(1):55. doi: 10.1186/s40478-023-01529-6.
The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known. Here, we evaluated transgenic APP/PS1 mouse model of AD and wild-type mice at 6- and 12-month-old, as early and late pathological stage, respectively. We noticed the alteration of circadian clock gene expression not only in the hypothalamus but also in two extra-hypothalamic brain regions, cerebral cortex and hippocampus, in APP/PS1 mice. These alterations were observed in 6-month-old transgenic mice and were exacerbated at 12 months of age. This could be explained by the reduced RHT projections in the SCN of APP/PS1 mice, correlating with downregulation of hypothalamic GABAergic response in APP/PS1 mice in advanced stage of pathology. Importantly, we also report retinal degeneration in APP/PS1 mice, including Aβ deposits and reduced choline acetyltransferase levels, loss of melanopsin retinal ganglion cells and functional integrity mainly of inner retina layers. Our findings support the theory that retinal degeneration constitutes an early pathological event that directly affects the control of circadian rhythm in AD.
生物钟通过环境光与 24 小时的昼夜同步，环境光主要通过视网膜下丘脑束（RHT）从视网膜传递到视交叉上核（SCN）。在神经退行性疾病如阿尔茨海默病（AD）中已经报道了昼夜节律异常。这些与 AD 相关的变化是由于时钟基因表达的改变、视网膜变性（包括 RHT 传递功能障碍）、视网膜神经节细胞及其电生理功能的丧失，还是所有这些病理机制的组合造成的，目前尚不清楚。在这里，我们评估了 AD 的转基因 APP/PS1 小鼠模型和野生型小鼠，分别在 6 个月和 12 个月大时，作为早期和晚期病理阶段。我们注意到，不仅在 SCN 中，而且在两个额外的下丘脑脑区——大脑皮层和海马体中，AD 转基因小鼠的昼夜节律基因表达也发生了改变。这些改变在 6 个月大的转基因小鼠中就已经观察到，并在 12 个月时加剧。这可以用 APP/PS1 小鼠 SCN 中的 RHT 投射减少来解释，这与 AD 病理晚期 APP/PS1 小鼠中下丘脑 GABA 能反应的下调有关。重要的是，我们还报告了 APP/PS1 小鼠的视网膜变性，包括 Aβ 沉积和胆碱乙酰转移酶水平降低、黑视素视网膜神经节细胞丧失以及主要是内视网膜层的功能完整性丧失。我们的发现支持这样一种理论，即视网膜变性是一种直接影响 AD 中昼夜节律控制的早期病理事件。
