Huang Ziyi, Wang Lei
Scholastic Excellence Research Center, Wuxi Dipont School of Arts and Science, Wuxi, China.
Front Comput Neurosci. 2025 Jul 22;19:1643547. doi: 10.3389/fncom.2025.1643547. eCollection 2025.
Memory impairment is a prevalent symptom in patients with Alzheimer's disease (AD), with working memory loss being the most prominent deficit. Recent experimental evidence suggests that abnormal calcium levels in the Endoplasmic Reticulum (ER) may disrupt synaptic transmission, leading to memory loss in AD patients. However, the specific mechanisms by which intracellular calcium homeostasis influences memory formation, storage, and recall in the context of AD remain unclear. In this study, we investigate the effects of intracellular calcium homeostasis on AD-related working memory (WM) using a spiking network model. We quantify memory storage by measuring the similarity between images during the training and testing phases. The model results indicate that ~90% of memory can be stored in the WM network under normal conditions. In contrast, the presence of amyloid beta (β), associated with AD, significantly reduces this similarity, allowing only 54%-58% of memory to be stored, this alteration trend is consistent with previous experimental findings. Further analysis reveals that downregulating the activation of inositol triphosphate ( ) receptors and upregulating the activation of the sarco-endoplasmic reticulum ATPase () pumps can enhance memory performance, achieving about 78% and 77%, respectively. Moreover, simultaneously manipulating both and activations can increase memory capacity to around 81%. These findings suggest several potential therapeutic targets for addressing memory impairment in β aggregation induced AD patients. Additionally, our network model could serve as a foundation for exploring further mechanisms that modulate memory dysfunction at the genetic, cellular, and network levels.
记忆障碍是阿尔茨海默病（AD）患者中普遍存在的症状，其中工作记忆丧失是最突出的缺陷。最近的实验证据表明，内质网（ER）中异常的钙水平可能会破坏突触传递，导致AD患者出现记忆丧失。然而，在AD背景下，细胞内钙稳态影响记忆形成、存储和回忆的具体机制仍不清楚。在本研究中，我们使用脉冲神经网络模型研究细胞内钙稳态对AD相关工作记忆（WM）的影响。我们通过测量训练和测试阶段图像之间的相似度来量化记忆存储。模型结果表明，在正常情况下，约90%的记忆可以存储在WM网络中。相比之下，与AD相关的β淀粉样蛋白（Aβ）的存在显著降低了这种相似度，仅允许54%-58%的记忆被存储，这种变化趋势与先前的实验结果一致。进一步分析表明，下调肌醇三磷酸（IP3）受体的激活并上调肌浆内质网ATP酶（SERCA）泵的激活可以提高记忆性能，分别达到约78%和77%。此外，同时操纵IP3和SERCA的激活可以将记忆容量提高到约81%。这些发现为解决Aβ聚集诱导的AD患者的记忆障碍提出了几个潜在的治疗靶点。此外，我们的网络模型可以作为探索在基因、细胞和网络水平上调节记忆功能障碍的进一步机制的基础。
