Tao Xiaoxiao, Kumar Udaya, Wang Miaomiao, Manglani Kapil, Zhu Cansheng, Jones Mychica R, Bombino Alexander, Bragin Anatol, Cole Gregory, Vossel Keith, Engel Jerome, Frautschy Sally A, Li Lin
Department of Biomedical Engineering, University of North Texas, Denton, TX, 76207, USA.
Department of Neurology, University of California, Los Angeles, CA, 90095, USA.
Alzheimers Res Ther. 2025 Sep 1;17(1):200. doi: 10.1186/s13195-025-01841-4.
Alzheimer's disease (AD) is one of the most prevalent causes of dementia, characterized by progressive memory loss and cognitive decline. Abnormal electrophysiological patterns, especially interictal epileptiform discharges (IEDs) and high-frequency oscillations (HFOs), have been observed in mouse models of AD and are suggested to contribute to cognitive dysfunction. However, comprehensive evaluations of IEDs across different brain regions are limited, and their impact on cognitive performance and neuropathology remains unclear, particularly in more complex AD models with relevant comorbidities. To address this gap, our study aims to clarify how IEDs and HFOs contribute to cognitive decline and neuropathology in AD, potentially informing the development of new biomarkers for early detection.
We investigate these effects in an AD (PS1/APP) rat model (FAD+) with coexisting hypertension-associated small vessel disease (SVD), as well as in their transgene-negative littermates (FAD-). We conducted behavioral experiments at 6, 8, and 11 months of animal age, alongside neural signal recordings at 8 and 11 months. AD pathology (neuritic plaques and hyperphosphorylated tau) and novel biomarkers (14-3-3γ) or biomarkers common to both disorders (neuropeptide Y, astrocyte and microglia) were evaluated at the end of the experiment.
Seizures were observed in three out of 14 FAD + rats. IED rates were significantly greater in FAD + rats compared to FAD- at all tested periods, correlating with changes in neuropathological biomarkers. Furthermore, coupling strength between IEDs and HFOs was significantly elevated in FAD + rats, especially during the later stages of disease progression. In addition, FAD + rats exhibited deficits in both learning and recall abilities at both ages, which correlated most strongly with increased IED-HFO coupling strength. No such correlation was observed in the FAD- group.
Our findings suggest that pathological synchronization between IEDs and HFOs in the hippocampus, along with neuropathological changes in both the hippocampus and entorhinal cortex, may contribute to memory dysfunction in AD, highlighting a potential mechanistic link between epileptiform activity, AD biomarker changes, and cognitive decline.
阿尔茨海默病（AD）是痴呆最常见的病因之一，其特征为进行性记忆丧失和认知衰退。在AD小鼠模型中观察到了异常的电生理模式，尤其是发作间期癫痫样放电（IEDs）和高频振荡（HFOs），并提示它们会导致认知功能障碍。然而，对不同脑区IEDs的全面评估有限，其对认知表现和神经病理学的影响仍不清楚，尤其是在具有相关合并症的更复杂AD模型中。为填补这一空白，我们的研究旨在阐明IEDs和HFOs如何导致AD中的认知衰退和神经病理学变化，这可能为早期检测的新生物标志物的开发提供依据。
我们在患有高血压相关小血管疾病（SVD）的AD（PS1/APP）大鼠模型（FAD+）及其转基因阴性同窝大鼠（FAD-）中研究这些影响。我们在动物6、8和11个月大时进行行为实验，并在8和11个月时进行神经信号记录。在实验结束时评估AD病理学（神经炎性斑块和过度磷酸化tau）以及新生物标志物（14-3-3γ）或两种疾病共有的生物标志物（神经肽Y、星形胶质细胞和小胶质细胞）。
在14只FAD+大鼠中有3只出现癫痫发作。在所有测试时期，FAD+大鼠的IED发生率均显著高于FAD-大鼠，且与神经病理学生物标志物的变化相关。此外，FAD+大鼠中IEDs与HFOs之间的耦合强度显著升高，尤其是在疾病进展的后期。此外，FAD+大鼠在两个年龄段的学习和回忆能力均表现出缺陷，这与IED-HFO耦合强度增加的相关性最强。在FAD-组中未观察到这种相关性。
我们的研究结果表明，海马中IEDs与HFOs之间的病理同步，以及海马和内嗅皮质的神经病理学变化，可能导致AD中的记忆功能障碍，突出了癫痫样活动、AD生物标志物变化和认知衰退之间潜在的机制联系。
