Synaptic dysfunction associated with changes in biophoton activity and survival-death signals is a shared mechanism in early AD and VaD

Although clinically, Alzheimer's disease (AD) and vascular dementia (VaD) are considered two different types of dementia, it is unclear whether the cellular and molecular mechanisms of cognitive impairment related to these diseases have common features. Here, by using an ultraweak biophoton imaging system (UBIS) and synaptosomes isolated from early AD and VaD models, we found that biophotonic activity induced by glutamate was significantly decreased and blueshifted due to glutamate aggregation at synapses and changes in GluN2B-containing N-methyl-D-aspartate receptor (NMDAR) expression. Such changes could be partially reversed by ifenprodil, a specific antagonist of the GluN2B subunit of NMDAR. Additionally, the expression of BDNF, mTOR and Arc was decreased, while the expression of caspase3 was increased in synaptosomes from AD and VaD models. These findings suggest that in AD and VaD pathology, synaptic dysfunction is not only related to abnormal signal transmission but also associated with alterations in neuronal survival-death signals in synaptosomes, implying that AD and VaD may involve similar but complex changes in synaptic function and structure and the expression of related signalling molecules, which need to be further studied.尽管临床上阿尔茨海默病（Alzheimer's disease, AD）与血管性痴呆（vascular dementia, VaD）被视为两种不同的痴呆亚型，但目前仍不清楚这两种疾病相关认知损害的细胞与分子机制是否存在共同特征。本研究借助超弱生物光子成像系统（ultraweak biophoton imaging system, UBIS），并使用从早期AD及VaD模型中分离的突触小体（synaptosomes）开展实验，发现谷氨酸（glutamate）诱导的生物光子活性显著降低且发生蓝移（blueshift），该现象源于突触处谷氨酸聚集以及含GluN2B亚基的N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptor, NMDAR）表达的改变。此类变化可被艾芬地尔（ifenprodil）——一种NMDAR的GluN2B亚基特异性拮抗剂——部分逆转。此外，在AD及VaD模型的突触小体中，脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）、哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）以及活动调节细胞骨架蛋白（activity-regulated cytoskeleton-associated protein, Arc）的表达水平均出现下调，而半胱氨酸天冬氨酸蛋白酶3（caspase3）的表达水平则有所升高。上述研究结果表明，在AD与VaD的病理进程中，突触功能障碍不仅与信号转导异常相关，还与突触小体内神经元存活-死亡信号的改变有关；这提示AD与VaD可能在突触功能、结构以及相关信号分子表达方面存在相似却复杂的变化，该结论仍有待进一步深入研究。